Composition and methods for stimulating gastrointestinal motility

ABSTRACT

The present invention is directed to methods for stimulating the motility of the gastrointestinal system in a patient which comprises administering a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of said secretagogue or said prodrug. More particularly, the present invention provides methods for stimulating the motility of the gastrointestinal system in a patient which comprises administering a compound of Formula I:  
                 
 
     a prodrug thereof or a pharmaceutically acceptable salt of said secretagogue or said prodrug.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/208,234, filed May 31, 2000.

FIELD OF THE INVENTION

[0002] The present invention provides methods of using growth hormonesecretagogues, prodrugs thereof and pharmaceutically acceptable salts ofsaid secretagogues and said prodrugs, as stimulators of the motility ofthe gastrointestinal system in patients. More specifically, the presentinvention provides methods of using compounds of Formula I below asstimulators of the motility of the gastrointestinal system in patients.In addition, the present invention provides methods of treatingconditions of impaired gastrointestinal motility, such asgastroesophageal reflux disease, gastroparesis (e.g., as a complicationof diabetes), emesis (e.g., that caused by cancer chemotherapy agents),postoperative ileus, constipation (e.g., that associated with thehypomotility phase of irritable bowel syndrome) and colonicpseudo-obstruction. The present invention also provides pharmaceuticalcompositions and kits for the above uses.

BACKGROUND OF THE INVENTION

[0003] Gastrointestinal (GI) motility is a coordinated neuromuscularprocess that transports nutrients through the digestive system. C.Scarpignato, Dig. Dis. 15: 112 (1997). Impaired GI motility, which maybe involved in gastroesophageal reflux disease, gastroparesis (e.g.,diabetic and postsurgical), irritable bowel syndrome and constipation,is one of the largest health care burdens of industralized nations. S.D. Feighner et al., Science 284: 2184-2188 (Jun. 25, 1999). Impaired GImotility can also lead to emesis (e.g., that caused by cancerchemotherapy agents), postoperative ileus and colonicpseudo-obstruction.

[0004] Very few compounds are known in the art to be useful for treatingimpaired GI motility. For example, PROPULSID® which contains cisapridemonohydrate is an oral gastrointestinal agent (see U.S. Pat. No.4,962,115). It is indicated for the symptomatic treatment of adultpatients with nocturnal heartburn due to gastroesophageal refluxdisease. Other prokinetic agents include, for example, metoclopramide,erythromycin, domperidone, ondansetron, tropisetron, mosapride anditopride. However, these therapeutic regimens suffer from numerousproblems. For instance, PROPULSID® was recently removed from the marketdue to its potential to induce cardiac arrhythmias. A more effective,physiological way to stimulate GI motility would be highly desirable.

[0005] Growth hormone, which is secreted from the pituitary, stimulatesgrowth of all tissues of the body that are capable of growing. Inaddition, growth hormone is known to have the following basic effects onthe metabolic processes of the body: (1) increased rate of proteinsynthesis in all cells of the body; (2) decreased rate of carbohydrateutilization in cells of the body; and (3) increased mobilization of freefatty acids and use of fatty acids for energy. As is known to thoseskilled in the art, the known and potential uses of growth hormone arevaried and multitudinous. See “Human Growth Hormone,” Strobel andThomas, Pharmacological Reviews, 46, pg. 1-34 (1994). Also, these varieduses of growth hormone are summarized in International PatentApplication, Publication Number WO 97/24369.

[0006] Various ways are known to release growth hormone (see RecentProgress in Hormone Research, vol. 52, pp. 215-245 (1997); and FrontHorm Res. Basel, Karger, vol. 24, pp. 152-175 (1999)). For example,chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA),glucagon, vasopressin, and insulin induced hypoglycemia, as well asactivities such as sleep and exercise, indirectly cause growth hormoneto be released from the pituitary by acting in some fashion on thehypothalamus perhaps either to decrease somatostatin secretion or toincrease secretion of growth hormone releasing factor (GRF) or ghrelin(see Nature, vol. 402, pp. 656-660 (Dec. 9, 1999)), or all of these.

[0007] In cases where increased levels of growth hormone were desired,the problem was generally solved by providing exogenous growth hormoneor by administering GRF, IGF-I or a peptidyl compound which stimulatedgrowth hormone production and/or release. In any case, the peptidylnature of the compound necessitated that it be administered byinjection. Initially, the source of growth hormone was the extraction ofthe pituitary glands of cadavers. This resulted in a very expensiveproduct and carried with it the risk that a disease associated with thesource of the pituitary gland could be transmitted to the recipient ofthe growth hormone. Recombinant growth hormone has become availablewhich, while no longer carrying any risk of disease transmission, isstill a very expensive product which must be given by injection. Inaddition, administration of exogenous growth hormone may result inside-effects, including edema, and does not correlate with the pulsatilerelease seen in the endogenous release of growth hormone.

[0008] Certain compounds have been developed which stimulate the releaseof endogenous growth hormone. Peptides which are known to stimulate therelease of endogenous growth hormone include growth hormone releasinghormone and its analogs, the growth hormone releasing peptides, GHRP-6and GHRP-1 (described in U.S. Pat. No. 4,411,890; International PatentApplication, Publication No. WO 89/07110; and International PatentApplication, Publication No. WO 89/07111), and GHRP-2 (described inInternational Patent Application, Publication No. WO 93/04081), as wellas hexarelin (J. Endocrinol. Invest., 15 (Suppl. 4): 45 (1992)). Othercompounds possessing growth hormone secretagogue activity are disclosedin the following International Patent Applications (listed byPublication Nos.), issued U.S. Patents and published European PatentApplications: WO 98/46569, WO 98/51687, WO 98/58947, WO 98/58949, WO98/58950, WO 99/08697, WO 99/09991, WO 95/13069, U.S. Pat. No.5,492,916, U.S. Pat. No. 5,494,919, WO 95/14666, WO 94/19367, WO94/13696, WO 94/11012, U.S. Pat. No. 5,726,319, WO 95/11029, WO95/17422, WO 95/17423, WO 95/34311, WO 96/02530, WO 96/22996, WO96/22997, WO 96/24580, WO 96/24587, U.S. Pat. No. 5,559,128, WO96/32943, WO 96/33189, WO 96/15148, WO 96/38471, WO 96/35713, WO97/00894, WO 97/07117, WO 97/06803, WO 97/11697, WO 97/15573, WO97/22367, WO 97/23508, WO 97/22620, WO 97/22004, WO 97/21730, WO97/24369, U.S. Pat. No. 5,663,171, WO 97/34604, WO 97/36873, WO97/40071, WO 97/40023, WO 97/41878, WO 97/41879, WO 97/46252, WO97/44042, WO 97/38709, WO 98/03473, WO 97/43278, U.S. Pat. No.5,721,251, U.S. Pat. No. 5,721,250, WO 98/10653, U.S. Pat. No.5,919,777, U.S. Pat. No. 5,830,433 and EP 0995748.

[0009] In addition, the following growth hormone secretagogues are knownin the art: MK-0677, L-162752 and L-163022 (Merck); NN703 and ipamorelin(Novo Nordisk); hexarelin (Pharmacia & Upjohn); GPA-748 (KP102, GHRP-2)(American Home Products); and LY444711 (Eli Lilly). The following agentsthat stimulate GH release via GHRH/GRF receptor (including GHRH/GRFderivatives, analogs and mimetics) are known in the art: Geref(Ares/Serono); GHRH (1-44) (BioNebraska); Somatorelin (GRF 1-44)(Fujisawa/ICN); and ThGRF (Theratechnologies).

[0010] Endocrine Reviews 18(5): 621-645 (1997) provides an overview ofpeptidomimetic regulation of growth hormone secretion by growth hormonesecretagogues. Horm. Res. 1999; 51(suppl 3):16-20 (1999), examines theclinical and experimental effects of growth hormone secretagogues onvarious organ systems. Drug Discovery Today, Vol. 4, No. 11, November1999; and TEM Vol. 10, No. 1, 1999, disclose potential therapeuticapplications of growth hormone secretagogues, including their use intreating growth hormone disorders such as growth hormone deficiency(GHD), age-related conditions, obesity and catabolic conditions, andtheir use in sleep enhancement.

[0011] International Patent Applications, Publication Nos. WO 97/24369and WO 98/58947 disclose that certain growth hormone secretagogues areuseful for the treatment or prevention of osteoporosis, congestive heartfailure, frailty associated with aging, obesity; accelerating bonefracture repair, attenuating protein catabolic response after a majoroperation, reducing cachexia and protein loss due to chronic illness,accelerating wound healing or accelerating the recovery of burn patientsor patients having undergone major surgery; improving muscle strength,mobility, maintenance of skin thickness, metabolic homeostasis or renalhomeostasis. Published European patent application 0995748 disclosesthat certain dipeptide growth hormone secretagogues are useful for thetreatment or prevention of musculoskeletal frailty, includingosteoporosis.

[0012] The administration of a growth hormone secretagogue is also knownto enhance the quality of sleep, which is disclosed in InternationalPatent Application, Publication No. WO 97/24369. A growth hormonesecretagogue can be administered to a patient having or at risk ofhaving one or more of the conditions or symptoms recited above. Commonlyassigned U.S. nonprovisional patent application Ser. No. 09/290985,filed Apr. 13, 1999, discloses pharmaceutical compositions comprisingcertain β₃ adrenergic agonists and growth hormone secretagogues orgrowth hormone, and their use for treating diabetes, obesity,hyperglycemia, frailty associated with obesity or frailty associatedwith aging, and for enhancing the quality of sleep in a mammal.International Patent Application, Publication No. WO 98/58949, disclosesthe treatment of insulin resistance with certain growth hormonesecretagogues.

[0013] Abstract OR4-5 from The Endocrine Society 81^(st) Annual Meeting(Jun. 12-15, 1999), San Diego, Calif., discloses that growth hormone(GH) therapy resulted in marked clinical improvement in patients withactive Crohn's disease (regional inflammation of the intestines).

[0014] S. D. Feighner et al., Science 284: 2184-2188 (Jun. 25, 1999),discloses that a heterotrimeric guanosine triphosphate-binding protein(G protein)-coupled receptor for motilin (a 22-amino acid peptidehormone expressed throughout the gastrointestinal tract of humans andother species) was isolated from the human stomach, and that its aminoacid sequence was found to be 52 percent identical to the human receptorfor growth hormone secretagogues.

SUMMARY OF THE INVENTION

[0015] The present invention provides a method of stimulating themotility of the gastrointestinal system in a patient which comprisesadministering to the patient a gastrointestinal motility stimulatingeffective amount of a growth hormone secretagogue.

[0016] More particularly, it provides such method wherein the growthhormone secretagogue is an orally active growth hormone secretagogue.Even more particularly, it provides such method wherein the growthhormone secretagogue is orally administered.

[0017] More particularly, it provides such method wherein the growthhormone secretagogue is a non-peptidyl growth hormone secretagogue.

[0018] More particularly, it provides such method wherein the patient isa human.

[0019] The present invention provides a method of stimulating themotility of the gastrointestinal system in a patient which comprisesadministering to the patient a gastrointestinal motility stimulatingeffective amount of a Compound of the Formula I:

[0020] or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, or a tautomer thereof, wherein

[0021] HET is a heterocyclic moiety selected from the group consistingof

[0022] d is 0, 1 or 2;

[0023] e is 1 or 2;

[0024] f is 0or 1;

[0025] n and w are 0, 1 or 2, provided that n and w cannot both be 0 atthe same time;

[0026] Y² is oxygen or sulfur;

[0027] A is a divalent radical, where the left hand side of the radicalas shown below is connected to C″ and the right hand side of the radicalas shown below is connected to C′, selected from the group consisting of

[0028] —NR²—C(O)—NR²—, —NR²—S(O)₂—NR², —O—C(O)—NR², —NR²—C(O)—O—,—C(O)—NR²—C(O)—, —C(O)—NR²—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—O—C(O)—, —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—, —NR²—C(O)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(O)—NR²—, —C(R⁹R¹⁰)—C(O)—O—,—C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—C(O)—,—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—, —C(R⁹R¹⁰)—NR²—C(O)—O—, —C(R⁹R¹⁰)—O—O—C(O)—NR²,—C(R⁹R¹⁰)—NR²—C(O)—NR²—, —NR²—C(O)—O—C(R⁹R¹⁰)—, —NR²—C(O)—NR²—C(R⁹R¹⁰)—,—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—, —O—C(O)—NR²—C(R⁹R¹⁰)—, C(O)—N═C(R¹¹)—NR²—,—C(O)—NR²—C(R¹¹)═N—, —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—,—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—NR²—C(R¹¹)═N—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,—C(R⁹R¹⁰)—NR¹²—N═C(R¹¹)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—, —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—;

[0029] Q is a covalent bond or CH₂;

[0030] W is CH or N;

[0031] X is CR⁹R¹⁰, C═CH₂ or C═O;

[0032] Y is CR⁹R¹⁰, O or NR²;

[0033] Z is C═O, C═S or S(O)₂;

[0034] G¹ is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl,carboxyl, —CONH₂, -(C₁-C₄)alkyl optionally independently substitutedwith one or more phenyl, one or more halogens or one or more hydroxygroups, -(C₁-C₄)alkoxy optionally independently substituted with one ormore phenyl, one or more halogens or one or more hydroxy groups,-(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl, N,N-di-(C₁-C₄)alkylamino,-(C₂-C₆)alkenyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,-(C₂-C₆)alkynyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,-(C₃-C₆)cycloalkyl optionally independently substituted with one or more(C₁-C₄)alkyl groups, one or more halogens or one or more hydroxy groups,-(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G² and G³are each independently selected from the group consisting of hydrogen,halo, hydroxy, -(C₁-C₄)alkyl optionally independently substituted withone to three halo groups and -(C₁-C₄)alkoxy optionally independentlysubstituted with one to three halo groups;

[0035] R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;

[0036] where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;

[0037] Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—,—C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

[0038] q is 0, 1, 2, 3 or 4;

[0039] t is 0, 1, 2 or 3;

[0040] said (CH₂)_(q) group and (CH₂)_(t) group in the definition of R¹are optionally independently substituted with hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups;

[0041] R^(1A) is selected from the group consisting of hydrogen, F, Cl,Br, I, (C₁-C₆)alkyl, phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl,thiazolyl(C₁-C₃)alkyl and thienyl(C₁-C₃)alkyl, provided that R^(1A) isnot F, Cl, Br or I when a heteroatom is vicinal to C″;

[0042] R² is hydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹;

[0043] where the alkyl groups and the cycloalkyl groups in thedefinition of R² are optionally substituted with hydroxy, —C(O)OX⁶,—C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶),CF₃, CN or 1, 2 or 3 independently selected halo groups;

[0044] R³ is selected from the group consisting of A¹, (C₁-C₁₀)alkyl,-(C₁-C₆)alkyl-A¹, -(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, -(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ and-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

[0045] where the alkyl groups in the definition of R³ are optionallysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5independently selected halo groups or 1, 2 or 3 independently selected—OX³ groups;

[0046] X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—;

[0047] R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl, or R⁴ is takentogether with R³ and the carbon atom to which they are attached and form(C₅-C₇)cycloalkyl, (C₅-C₇)cycloalkenyl, a partially saturated or fullysaturated 4- to 8-membered ring having 1 to 4 heteroatoms independentlyselected from the group consisting of oxygen, sulfur and nitrogen, or isa bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, fused to a partially saturated, fullyunsaturated or fully saturated 5- or 6-membered ring, optionally having1 to 4 heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen;

[0048] X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴and the nitrogen atom to which X⁴ is attached and the carbon atom towhich R⁴ is attached and form a five to seven membered ring;

[0049] R⁶ is a bond or is

[0050] where a and b are each independently 0, 1, 2 or 3;

[0051] X⁵ and X^(5a) are each independently selected from the groupconsisting of hydrogen, CF₃, A¹ and optionally substituted (C₁-C₆)alkyl;

[0052] the optionally substituted (C₁-C₆)alkyl in the definition of X⁵and X^(5a) is optionally substituted with a substituent selected fromthe group consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

[0053] or the carbon bearing X⁵ or X^(5a) forms one or two alkylenebridges with the nitrogen atom bearing R⁷ and R⁸ wherein each alkylenebridge contains 1 to 5 carbon atoms, provided that when one alkylenebridge is formed then only one of X⁵ or X^(5a) is on the carbon atom andonly one of R⁷ or R⁸ is on the nitrogen atom and further provided thatwhen two alkylene bridges are formed then X⁵ and X^(5a) cannot be on thecarbon atom and R⁷ and R⁸ cannot be on the nitrogen atom;

[0054] or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen;

[0055] or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a bicyclic ring system consisting of apartially saturated or fully saturated 5- or 6-membered ring, optionallyhaving 1 or 2 heteroatoms independently selected from the groupconsisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6-membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen;

[0056] Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O;

[0057] or R⁶ is —(CR^(a)R^(b))_(a)—E—(CR^(a)R^(b))_(b)—, where the—(CR^(a)R^(b))_(a) group is attached to the carbonyl carbon of the amidegroup of the compound of formula I and the —(CR^(a)R^(b))_(b) group isattached to the terminal nitrogen atom of the compound of Formula I;

[0058] E is —O—, —S—, —CH═CH— or an aromatic moiety selected from

[0059] said aromatic moiety in the definition of E optionallysubstituted with up to three halo, hydroxy, —N(R^(c))(R^(c)),(C₁-C₆)alkyl or (C₁-C₆)alkoxy; R^(a) and R^(b) are, for each occurrence,independently hydrogen, (C₁-C₆)alkyl, trifluoromethyl, phenyl ormonosubstituted (C₁-C₆)alkyl where the substituents are imidazolyl,naphthyl, phenyl, indolyl, p-hydroxyphenyl, —OR^(c), S(O)_(m)R^(c),C(O)OR^(c), (C₃-C₇)cycloalkyl, —N(R^(c))(R^(c)), —C(O)N(R^(c))(R^(c)),or R^(a) or R^(b) may independently be joined to one or both of R⁷ or E(where E is other than O, S or —CH═CH—) to form an alkylene bridgebetween the terminal nitrogen and the alkyl portion of the R^(a) orR^(b) and the R⁷ or E group, wherein the bridge contains 1 to 8 carbonatoms; or R^(a) and R^(b) may be joined to one another to form a(C₃-C₇)cycloalkyl;

[0060] R^(c), for each occurrence, is independently hydrogen or(C₁-C₆)alkyl; a and b are independently 0, 1, 2 or 3, with the provisothat if E is —O— or —S—, b is other than 0 or 1 and with the furtherproviso that if E is —CH═CH—, b is other than 0;

[0061] R⁷ and R⁸ are each independently hydrogen or optionallysubstituted (C₁-C₆)alkyl;

[0062] where the optionally substituted (C₁-C₆)alkyl in the definitionof R⁷ and R⁸ is optionally independently substituted with A¹,—C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groups or 1 to 3(C₁-C₆)alkoxy groups; or

[0063] R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

[0064] where L is C(X²)(X²), S(O)_(m) or N(X²);

[0065] R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionallyindependently substituted with 1-5 halo groups;

[0066] R¹¹ is selected from the group consisting of (C₁-C₅)alkyl andphenyl optionally substituted with 1-3 substituents each independentlyselected from the group consisting of (C₁-C₅)alkyl, halo and(C₁-C₅)alkoxy;

[0067] R¹² is selected from the group consisting of(C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkyl where the alkylportion is optionally independently substituted by 1-5 halo groups;

[0068] A¹ for each occurrence is independently selected from the groupconsisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen and a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen, fusedto a partially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

[0069] A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy;

[0070] where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

[0071] the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halo groups, 1 to 3hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or 1 to 3(C₁-C₆)alkoxy groups;

[0072] X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl,furyl or thienyl, provided that when X¹² is not hydrogen, the X¹² groupis optionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

[0073] or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—;

[0074] L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

[0075] r for each occurrence is independently 1, 2 or 3;

[0076] X² for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl or optionally substituted (C₃-C₇)cycloalkyl,where the optionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or1-3 OX³ groups;

[0077] X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0078] X⁶ for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionallysubstituted (C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, whereoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X⁶ is optionally independentlymono- or di-substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl esteror 1H-tetrazol-5-yl; or

[0079] when there are two X⁶ groups on one atom and both X⁶ areindependently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member;

[0080] X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted withhydroxy;

[0081] m for each occurrence is independently 0, 1 or 2;

[0082] with the provisos that:

[0083] 1) X⁶ and X¹² cannot be hydrogen when attached to C(O) or S(O)₂in the form C(O)X⁶, C(O)X¹², S(O)₂X⁶ or S(O)₂X¹²; and

[0084] 2) when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.

[0085] More preferably, the present invention provides such methodwherein the compound is of the structural formula below, which isdesignated herein as Formula I-A

[0086] a racemic-diastereomeric mixture or an optical isomer of saidcompound or a pharmaceutically-acceptable salt or prodrug thereof, or atautomer thereof, wherein

[0087] f is 0;

[0088] n is 0 and w is 2, or n is 1 and w is 1, or n is 2 and w is 0;

[0089] Y is oxygen or sulfur;

[0090] R¹ is hydrogen, —CN, —(CH₂)_(q)N(X⁶)C(O)X⁶,—(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂X⁶, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹, —(CH₂)_(q)C(O)OX⁶,—(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶, —(CH₂)_(q)OC(O)X⁶,—(CH₂)_(q)OC(O)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)C(O)OX⁶, —(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;

[0091] where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro;

[0092] Y¹ is O, S(O)_(m), —C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—,—C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or —OC(O)—;

[0093] q is 0, 1, 2, 3 or 4;

[0094] t is 0, 1, 2 or 3;

[0095] said (CH₂)_(q) group and (CH₂)_(t) group may each be optionallysubstituted with hydroxyl, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro, or 1 or 2 (C₁-C₄)alkyl;

[0096] R² is hydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹;

[0097] where the alkyl groups and the cycloalkyl groups in thedefinition of R² are optionally substituted with hydroxyl, —C(O)OX⁶,—C(O)N(X⁸)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶),CF₃, CN or 1, 2 or 3 halogen;

[0098] R³ is A¹, (C₁-C₁₀)alkyl, -(C₁-C₆)alkyl-A¹,-(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl;

[0099] where the alkyl groups in the definition of R³ are optionallysubstituted with, —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5halogens, or 1, 2 or 3 OX³;

[0100] X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, -OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—;

[0101] R⁴ is hydrogen, (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl;

[0102] X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ is taken together with R⁴and the nitrogen atom to which X⁴ is attached and the carbon atom towhich R⁴ is attached and form a five to seven membered ring;

[0103] R⁶ is a bond or is

[0104] where a and b are independently 0, 1, 2 or 3;

[0105] X⁵ and X^(5a) are each independently selected from the groupconsisting of hydrogen, trifluoromethyl, A¹ and optionally substituted(C₁-C₆)alkyl;

[0106] the optionally substituted (C₁-C₆)alkyl in the definition of X⁵and X^(5a) is optionally substituted with a substituent selected fromthe group consisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²);

[0107] R⁷ and R⁸ are independently hydrogen or optionally substituted(C₁-C₆)alkyl;

[0108] where the optionally substituted (C₁-C₆)alkyl in the definitionof R⁷ and R⁸ is optionally independently substituted with A¹,—C(O)O—(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3hydroxy, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or

[0109] R⁷ and R⁸ can be taken together to form —(CH₂)_(r)—L—(CH₂)_(r)—;

[0110] where L is C(X²)(X²), S(O)_(m) or N(X²);

[0111] A¹ in the definition of R¹ is a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen, a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, having 1 to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen;

[0112] A¹ in the definition of R², R³, R⁶, R⁷ and R⁸ is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen;

[0113] A¹ for each occurrence is independently optionally substituted,in one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)SO₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl or tetrazolyl, provided that if A¹ isoptionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy;

[0114] where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl;

[0115] the optionally substituted (C₁-C₆)alkyl defined for X¹¹ isoptionally independently substituted with phenyl, phenoxy,(C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3hydroxy, 1 to 3 (C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy;

[0116] X¹² is hydrogen, (C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl,furyl or thienyl, provided that when X¹² is not hydrogen, the X¹² isoptionally substituted with one to three substituents independentlyselected from the group consisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃;

[0117] or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—;

[0118] where L¹ is C(X²)(X²), O, S(O)_(m) or N(X²);

[0119] r for each occurrence is independently 1, 2 or 3;

[0120] X² for each occurrence is independently hydrogen, optionallysubstituted (C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl,where the optionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³;

[0121] X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;

[0122] X⁶ is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenatedcycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently substituted by 1 or 2(C₁-C₄)alkyl, hydroxyl, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester, or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9- membered ring optionally having oxygen,sulfur or NX⁷;

[0123] X⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted withhydroxyl; and

[0124] m for each occurrence is independently 0, 1 or 2;

[0125] with the proviso that:

[0126] X⁶ and X¹² cannot be hydrogen when it is attached to C(O) or SO₂in the form C(O)X⁶, C(O)X¹², SO₂X⁶ or SO₂X¹²; and

[0127] when R⁶ is a bond then L is N(X²) and each r in the definition—(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3.

[0128] More preferably, the present invention provides such methodwherein the compound is2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,a prodrug thereof or a pharmaceutically acceptable salt of the compoundor the prodrug. Even more preferably, the present invention providessuch method wherein the compound is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,L-tartrate.

[0129] Also, more preferably, the present invention provides such methodwherein the compound is2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of the compoundor the prodrug. Even more preferably, the present invention providessuch method wherein the compound is the (L)-(+)-tartaric acid salt of2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide.

[0130] Also, more preferably, the present invention provides such methodwherein the compound is2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of the compoundor the prodrug. Even more preferably, the present invention providessuch method wherein the compound is the (L)-(+)-tartaric acid salt of2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.

[0131] The present invention provides such method which furthercomprises administering a prokinetic agent. More particularly, thepresent invention provides such method wherein the prokinetic agent isselected from the group consisting of cisapride monohydrate,metoclopramide, erythromycin, domperidone, ondansetron, tropisetron,mosapride and itopride.

[0132] The present invention provides such method which furthercomprises administering a recombinant growth hormone or a growth hormonesecretagogue selected from the group consisting of GHRP-6, GHRP-1,GHRP-2, growth hormone releasing factor, an analog of growth hormonereleasing factor, IGF-I and IGF-II.

[0133] In addition, the present invention provides a method ofstimulating gastrointestinal transit in a patient which comprisesadministering to the patient a gastrointestinal transit stimulatingeffective amount of a growth hormone secretagogue.

[0134] More particularly, the present invention provides such methodwherein the growth hormone secretagogue is an orally active growthhormone secretagogue. Even more particularly, the present inventionprovides such method wherein the growth hormone secretagogue is orallyadministered.

[0135] More particularly, the present invention provides such methodwherein the growth hormone secretagogue is a non-peptidyl growth hormonesecretagogue.

[0136] More particularly, the present invention provides such methodwherein the patient is a human.

[0137] The present invention provides a method of stimulatinggastrointestinal transit in a patient which comprises administering tothe patient a gastrointestinal transit stimulating effective amount of acompound of the Formula I, wherein the variables are as defined above.More preferably, the present invention provides such method wherein thecompound is of the Formula I-A wherein the variables are as definedabove.

[0138] Even more preferably, the present invention provides such methodwherein the compound is selected from the following:2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug;2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,L-tartrate;2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug; the (L)-(+)-tartaric acid salt of2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide;2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug; and the (L)-(+)-tartaric acid salt of2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.

[0139] The present invention provides such method which furthercomprises administering a prokinetic agent. More particularly, thepresent invention provides such method wherein the prokinetic agent isselected from the group consisting of cisapride monohydrate,metoclopramide, erythromycin, domperidone, ondansetron, tropisetron,mosapride and itopride.

[0140] The present invention provides such method which furthercomprises administering a recombinant growth hormone or a growth hormonesecretagogue selected from the group consisting of GHRP-6, GHRP-1,GHRP-2, growth hormone releasing factor, an analog of growth hormonereleasing factor, IGF-I and IGF-II.

[0141] In addition, the present invention provides a method for treatinga condition selected from the group consisting of gastroesophagealreflux disease, gastroparesis, postoperative ileus, emesis, constipationand colonic pseudo-obstruction in a patient which comprisesadministering to the patient a condition treating effective amount of agrowth hormone secretagogue. More particularly, the present inventionprovides such method wherein the condition is gastroesophageal refluxdisease, gastroparesis, postoperative ileus or emesis.

[0142] More particularly, the present invention provides such methodwherein the growth hormone secretagogue is an orally active growthhormone secretagogue. Even more particularly, the present inventionprovides such method wherein the growth hormone secretagogue is orallyadministered.

[0143] More particularly, the present invention provides such methodwherein the growth hormone secretagogue is a non-peptidyl growth hormonesecretagogue.

[0144] More particularly, the present invention provides such methodwherein the patient is a human.

[0145] The present invention provides a method for treating a conditionselected from the group consisting of gastroesophageal reflux disease,gastroparesis, postoperative ileus, emesis, constipation and colonicpseudo-obstruction in a patient which comprises administering to thepatient a condition treating effective amount of a compound of theFormula I, wherein the variables are as defined above. More preferably,the present invention provides such method wherein the compound is ofthe Formula I-A.

[0146] Even more preferably, the present invention provides such methodwherein the compound is selected from the following:2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug;2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,L-tartrate;2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug; the (L)-(+)-tartaric acid salt of2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide;2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug; and the (L)-(+)-tartaric acid salt of2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.

[0147] The present invention provides such method which furthercomprises administering a prokinetic agent. More particularly, thepresent invention provides such method wherein the prokinetic agent isselected from the group consisting of cisapride monohydrate,metoclopramide, erythromycin, domperidone, ondansetron, tropisetron,mosapride and itopride.

[0148] The present invention provides such method which furthercomprises administering a recombinant growth hormone or a growth hormonesecretagogue selected from the group consisting of GHRP-6, GHRP-1,GHRP-2, growth hormone releasing factor, an analog of growth hormonereleasing factor, IGF-I and IGF-II.

[0149] The present invention provides a pharmaceutical compositioncomprising a compound of Formula I, an isomer thereof, a prodrug of saidcompound or isomer, or a pharmaceutically acceptable salt of saidcompound, isomer or prodrug, or a tautomer thereof, as defined above;and an additional compound useful to treat a condition selected from thegroup consisting of gastroesophageal reflux disease, gastroparesis,postoperative ileus, emesis, constipation and colonicpseudo-obstruction. More particularly, the present invention providessuch composition wherein the condition is gastroesophageal refluxdisease, gastroparesis, postoperative ileus or emesis.

[0150] The present invention provides such composition wherein theadditional compound is a prokinetic agent. More particularly, thepresent invention provides such composition wherein the prokinetic agentis selected from the group consisting of cisapride monohydrate,metoclopramide, erythromycin, domperidone, ondansetron, tropisetron,mosapride and itopride.

[0151] Finally, the present invention provides a kit for treating acondition selected from the group consisting of gastroesophageal refluxdisease, gastroparesis, postoperative ileus, emesis, constipation andcolonic pseudo-obstruction, the kit comprising:

[0152] a) a first pharmaceutical composition comprising a compound ofFormula I, an isomer thereof, a prodrug of said compound or isomer, apharmaceutically acceptable salt of said compound, isomer or prodrug, ora tautomer thereof, as defined above;

[0153] b) a second pharmaceutical composition comprising an additionalcompound useful for treating a condition selected from the groupconsisting of gastroesophageal reflux disease, gastroparesis,postoperative ileus, emesis, constipation and colonicpseudo-obstruction; and

[0154] c) a container.

DETAILED DESCRIPTION OF THE INVENTION

[0155] The present invention is directed to a method for stimulating themotility of the gastrointestinal system. In particular, the presentinvention provides a method for stimulating the motility of thegastrointestinal system comprising the administration of a growthhormone secretagogue. More particularly, the present invention providesa method for stimulating the motility of the gastrointestinal systemcomprising the administration of a compound of Formula I.

[0156] In view of their ability to stimulate gastrointestinal (GI)motility, the compounds of the present invention may be useful tonormalize or improve the gastric and/or intestinal transit and/oremptying in subjects suffering from a decreased peristalsis of thestomach and/or the small and/or large intestines, especially the stomachand the small intestines. Therefore, the compounds of the presentinvention may be useful to treat diseases of impaired GI motility suchas gastroesophageal reflux disease, gastroparesis (e.g., diabetic andpostsurgical), emesis (e.g., that caused by cancer chemotherapy agents),postoperative ileus, constipation (e.g., that associated with thehypomotility phase of irritable bowel syndrome) and colonicpseudo-obstruction. The compounds of the present invention may beespecially useful to treat diseases such as gastroesophageal refluxdisease, gastroparesis, emesis and postoperative ileus.

[0157] In the present invention, it is preferred that the patient is ahuman and is applicable to both old and young people.

[0158] By the term “growth hormone secretagogue” is meant anyexogenously administered compound or agent that directly or indirectlystimulates or increases the endogenous release of growth hormone, growthhormone-releasing hormone or somatostatin in an animal, in particular, ahuman. The growth hormone secretagogue may be peptidyl or non-peptidylin nature, however, the use of an orally active growth hormonesecretagogue is preferred. In addition, it is preferred that the growthhormone secretagogue induce or amplify a pulsatile release of endogenousgrowth hormone.

[0159] The expression “prodrug” refers to compounds that are drugprecursors which, following administration, release the drug in vivo viasome chemical or physiological process (e.g., a prodrug on being broughtto the physiological pH is converted to the desired drug form). Aprodrug of the compound of Formula I may be used in the presentinvention. Exemplary prodrugs are disclosed in the art, particularly inthe references cited herein and incorporated herein by reference.

[0160] The compound useful in the present invention may be used alone orin combination with one or more growth hormone secretagogues or with oneor more agents which are known to be beneficial for impaired GImotility. The compounds useful in the present invention and the otheragent may be coadministered, either in concomitant therapy or in a fixedcombination. For example, the compound may be administered incombination with other compounds which are known in the art to beprokinetic agents.

[0161] Representative growth hormone secretagogues are disclosed in thefollowing International Patent Applications (listed by PublicationNos.), issued U.S. patents and published European patent applications,which are incorporated herein by reference, WO 98/46569, WO 98/51687, WO98/58947, WO 98/58949, WO 98/58950, WO 99/08697, WO 99/09991, WO95/13069, U.S. Pat. No. 5,492,916, U.S. Pat. No. 5,494,919, WO 95/14666,WO 94/19367, WO 94/13696, WO 94/11012, U.S. Pat. No. 5,726,319, WO95/11029, WO 95/17422, WO 95/17423, WO 95/34311, WO 96/02530, WO96/22996, WO 96/22997, WO 96/24580, WO 96/24587, U.S. Pat. No.5,559,128, WO 96/32943, WO 96/33189, WO 96/15148, WO 96/38471, WO96/35713, WO 97/00894, WO 97/07117, WO 97/06803, WO 97/11697, WO97/15573, WO 97/22367, WO 97/23508, WO 97/22620, WO 97/22004, WO97/21730, WO 97/24369, U.S. Pat. No. 5,663,171, WO 97/34604, WO97/36873, WO 97/40071, WO 97/40023, WO 97/41878, WO 97/41879, WO97/46252, WO 97/44042, WO 97/38709, WO 98/03473, WO 97/43278, U.S. Pat.No. 5,721,251, U.S. Pat. No. 5,721,250, WO 98/10653, U.S. Pat. No.5,919,777, U.S. Pat. No. 5,830,433 and EP 0995748.

[0162] A representative first group of growth hormone secretagogues isset forth in International Patent Application, Publication No. WO97/24369, which is incorporated herein by reference, as compounds havingthe structural formula below, which is designated herein as Formula II:

[0163] wherein the various substituents are as defined in WO 97/24369.Said compounds are prepared as disclosed therein.

[0164]2-Amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,having the following structure:

[0165] and2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,having the following structure:

[0166] and the pharmaceutically acceptable salts thereof are within thescope of the disclosure of International Patent Application, PublicationNumber WO 97/24369.

[0167] A representative second group of growth hormone secretagogues isset forth in International Patent Application, Publication No. WO98/58947, which is incorporated by reference herein, as compounds havingthe structural formula below, which is designated herein as Formula III:

[0168] wherein the various substituents are as defined in WO 98/58947.Said compounds are prepared as disclosed therein or as described herein.

[0169] The most preferred compound within this second group which may beemployed in the present invention is identified as having the followingname and structure:2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide,

[0170] This compound is within the scope of the disclosure ofInternational Patent Application, Publication No. WO 98/58947, and maybe prepared as described in Examples Five and Six therein.

[0171] A representative third group of growth hormone secretagogues isset forth in Published European patent application 0995748, which ishereby incorporated by reference herein, which discloses certaindipeptide growth hormone secretagogues of the structural formula above,which is designated herein as Formula III, and their use for thetreatment or prevention of musculoskeletal fraility includingosteoporosis.

[0172] A representative fourth group of growth hormone secretagogues isset forth in U.S. Pat. No. 5,206,235, which is incorporated herein byreference, as having the following structure:

[0173] wherein the various substituents are as defined in U.S. Pat. No.5,206,235. Said compounds are prepared as disclosed therein.

[0174] The most preferred compounds within this fourth group areidentified as having the following structures:

[0175] A representative fifth group of growth hormone secretagogues isset forth in U.S. Pat. No. 5,283,241, which is incorporated herein byreference, as having the following structural formula:

[0176] wherein the various substituents are as defined in U.S. Pat.5,283,241. Said compounds are prepared as disclosed therein.

[0177] A representative sixth group of growth hormone secretagogues isdisclosed in International Patent Application, Publication No. WO97/41879, which is incorporated herein by reference, as compounds havingthe following structural formulas:

[0178] wherein the various substituents are as defined in WO97/41879.Said compounds are prepared as disclosed therein.

[0179] The most preferred compounds within this sixth group which may beemployed in the present invention are identified as having the followingstructure:

[0180] and pharmaceutically acceptable salts thereof, in particular, themethanesulfonate salt.

[0181] A representative seventh group of growth hormone secretagogues isdisclosed in U.S. Pat. No. 5,492,916, which is incorporated herein byreference, as being compounds of the following structural formula:

[0182] wherein the various substituents are as defined in U.S. Pat. No.5,492,916. Said compounds are prepared as disclosed therein.

[0183] All of the compounds identified above may be prepared byprocedures disclosed in the cited publications. Full descriptions of thepreparation of the compounds which may be employed in the presentinvention may be found in the art, particularly in the references citedherein, which are incorporated herein by reference.

[0184] The compounds of Formula I used in the methods of the presentinvention all have at least one asymmetric center as noted, e.g., by theasterisk in the structural Formula I-B below. Additional asymmetriccenters may be present in the compounds of Formula I depending upon thenature of the various substituents on the molecule. Each such asymmetriccenter will produce two optical isomers and it is intended that all suchoptical isomers, as separated, pure or partially purified opticalisomers, racemic mixtures or diastereomeric mixtures thereof, beincluded within the scope of the methods and combinations of the instantinvention. In the case of the asymmetric center represented by theasterisk, it has been found that the absolute stereochemistry of themore active and thus more preferred isomer is shown in Formula I-Bbelow:

[0185] With the R⁴ substituent as hydrogen, the spatial configuration ofthe asymmetric center corresponds to that in a D-amino acid. In mostcases this is also designated an R-configuration although this will varyaccording to the values of R³ and R⁴ used in making R- orS-stereochemical assignments.

[0186] Certain compounds within the scope of the present invention mayhave the potential to exist in different tautomeric forms. All tautomersof a compound of the present invention are within the scope of thepresent invention. Also, for example, all keto-enol or imine-enamineforms of the compounds are included in the present invention. Thoseskilled in the art will recognize that the compound names containedherein may be based on a particular tautomer of a compound. While thename for only a particular tautomer may be used, it is intended that alltautomers are encompassed by the name of the particular tautomer and alltautomers are considered part of the present invention.

[0187] A compound within the scope of the present invention may exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The present inventioncontemplates and encompasses both the solvated and unsolvated forms.

[0188] Also included within the scope of the present invention areisotopically-labelled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in compound and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples below, bysubstituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

[0189] Full descriptions of preparation of the compounds employed in thepresent invention may be found, for example, in the followingInternational Patent Applications (listed by Publication Nos.), issuedU.S. patents and published European patent applications, which areincorporated herein by reference, WO 98/46569, WO 98/51687, WO 98/58947,WO 98/58949, WO 98/58950, WO 99/08697, WO 99/09991, WO 95/13069, U.S.Pat. No. 5,492,916, U.S. Pat. No. 5,494,919, WO 95/14666, WO 94/19367,WO 94/13696, WO 94/11012, U.S. Pat. No. 5,726,319, WO 95/11029, WO95/17422, WO 95/17423, WO 95/34311, WO 96/02530, WO 96/22996, WO96/22997, WO 96/24580, WO 96/24587, U.S. Pat. No. 5,559,128, WO96/32943, WO 96/33189, WO 96/15148, WO 96/38471, WO 96/35713, WO97/00894, WO 97/07117, WO 97/06803, WO 97/11697, WO 97/15573, WO97/22367, WO 97/23508, WO 97/22620, WO 97/22004, WO 97/21730, WO97/24369, U.S. Pat. No. 5,663,171, WO 97/34604, WO 97/36873, WO97/40071, WO 97/40023, WO 97/41878, WO 97/41879, WO 97/46252, WO97/44042, WO 97/38709, WO 98/03473, WO 97/43278, U.S. Pat. No.5,721,251, U.S. Pat. No. 5,721,250, WO 98/10653, U.S. Pat. No.5,919,777, U.S. Pat. No. 5,830,433 and EP 0995748.

[0190] A growth hormone secretagogue is a compound that, whenadministered to a patient, increases the production and/or secretion ofgrowth hormone when compared with baseline plasma concentrations ofgrowth hormone in a normal healthy individual. Thus, to identify agrowth hormone secretagogue, one need simply measure the baseline plasmaconcentrations of growth hormone over a time period, typically one day,and compare the plasma concentrations of growth hormone afteradministration of a growth hormone secretagogue with the baselineconcentration over the time period. Various examples of growth hormonesecretagogues are disclosed herein. It is contemplated that any growthhormone secretagogue can be used in the present administration methods.

[0191] The identification of a compound as a “growth hormonesecretagogue” which is able to directly or indirectly stimulate orincrease the endogenous release of growth hormone in an animal may bereadily determined without undue experimentation by methodology wellknown in the art, such as the assay described by Smith et al., Science,260, 1640-1643 (1993) (see text of FIG. 2 therein). In a typicalexperiment, pituitary glands are aseptically removed from 150-200 gWistar male rats and cultures of pituitary cells are prepared accordingto Cheng et al., Endocrinol., 124, 2791-2798 (1989). The cells aretreated with the subject compound and assayed for growth hormonesecreting activity, as described by Cheng et al. (ibid.). In particular,the intrinsic growth hormone secretagogue activity of a compound whichmay be used in the present invention may be determined by this assay.

[0192] The particular application of growth hormone secretagogues in thepresent invention provides unexpected benefits relative to theadministration of exogenous growth hormone. In particular, the growthhormone secretagogue enhances the normal pulsatile release of endogenousgrowth hormone and thus is more likely to reproduce the natural patternof endogenous growth hormone release (see J. Clin. Endocrinol. Metab.81: 4249-4257, 1996). Growth hormone secretagogues which are orallyactive also have the benefit of being able to be administered orally,rather than just intravenously, intraperitoneally or subcutaneously. Theadvantage of this method is that, in contrast to injections of growthhormone, it provides a physiological-like pulsatile profile of growthhormone release from the pituitary gland.

[0193] The term “patient” means animals, such as humans, companionsanimals such as dogs, cats and horses, and livestock such as cattle,swine and sheep. Particularly preferred patients are mammals, includingboth males and females, with humans being even more preferred.

[0194] The term “pharmaceutically acceptable” means that a substance ormixture of substances must be compatible with the other ingredients of aformulation, and not deleterious to the patient.

[0195] The terms “treating”, “treat” or “treatment” include preventive(e.g., prophylactic) and palliative treatment.

[0196] The term “therapeutically effective amount” means an amount of acompound that ameliorates, attenuates, or eliminates a particulardisease or condition, or prevents or delays the onset of a disease orcondition.

[0197] In view of their use according to the present invention, thecompounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. A compound may beadministered, alone or in combination, by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous or subcutaneous injection,or implant), nasal, vaginal, rectal, sublingual, or topical routes ofadministration and can be formulated with pharmaceutically acceptablecarriers to provide dosage forms appropriate for each route ofadministration.

[0198] Solid dosage forms for oral administration include capsules,tablets, pills, powders and granules and for companion animals the soliddosage forms include an admixture with food and chewable forms. In suchsolid dosage forms, the compounds and combinations of this invention canbe admixed with at least one inert pharmaceutically acceptable carriersuch as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than suchinert diluents, e.g., lubricating agents such as magnesium stearate. Inthe case of capsules, tablets and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills can additionally beprepared with enteric coatings. In the case of chewable forms, thedosage form may comprise flavoring agents and perfuming agents.

[0199] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater. Besides such inert diluents, compositions can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,and sweetening, flavoring and perfuming agents.

[0200] Preparations according to this invention for parenteraladministration include sterile aqueous or non-aqueous solutions,suspensions, or emulsions. Examples of non-aqueous solvents or vehiclesare propylene glycol, polyethylene glycol, vegetable oils, such as oliveoil and corn oil, gelatin, and injectable organic esters such as ethyloleate. Such dosage forms may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. They may be sterilized by,for example, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

[0201] Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as cocoa butter or a suppository wax. Compositions fornasal or sublingual administration are also prepared with standardexcipients well known in the art.

[0202] The dosage of active ingredients in the compositions, methods andcombinations of the present invention invention may be varied; however,it is necessary that the amount of the active ingredients be such that asuitable dosage form is obtained. The selected dosage depends upon thedesired therapeutic effect, on the route of administration, and on theduration of the treatment. Generally, dosage levels of between 0.0001 to100 mg/kg of body weight daily are administered to humans and otheranimals, e.g., mammals. A preferred dosage range in humans is 0.01 to5.0 mg/kg of body weight daily which can be administered as a singledose or divided into multiple doses.

[0203] A preferred dosage range in animals other than humans is 0.01 to10.0 mg/kg of body weight daily which can be administered as a singledose or divided into multiple doses. A more preferred dosage range inanimals other than humans is 0.1 to 5 mg/kg of body weight daily whichcan be administered as a single dose or divided into multiple doses.

[0204] Where the tartrate salt or other pharmaceutically acceptable saltof the above compounds is used in the present invention, the skilledperson will be able to calculate effective dosage amounts by calculatingthe molecular weight of the salt form and performing simplestoichiometric ratios.

[0205] Also, the present invention includes within its scope the use ofa compound according to the present invention, alone or in combinationwith a growth hormone secretagogue, such as those referenced herein,including the growth hormone releasing peptides GHRP-6 and GHRP-1(described in U.S. Pat. No. 4,411,890 and International PatentApplications, Publication Nos. WO 89/07110, WO 89/07111), GHRP-2(described in WO 93/04081) and B-HT920, as well as hexarelin and growthhormone releasing hormone (GHRH, also designated GRF) and its analogs,growth hormone and its analogs and somatomedins including IGF-I andIGF-II, or in combination with other therapeutic agents, such asα-adrenergic agonists such as clonidine or serotonin 5-HT1D agonistssuch as sumatriptan, or agents which inhibit somatostatin or its releasesuch as physostigmine and pyridostigmine. Preferably, the compound maybe used in combination with growth hormone releasing factor, an analogof growth hormone releasing factor IGF-1 or IGF-II.

[0206] Methods to obtain the growth hormone releasing peptides GHRP-6and GHRP-1 are described in U.S. Pat. No. 4,411,890 and PCT PatentPublications WO 89/07110, WO 89/07111, methods to obtain the growthhormone releasing peptide GHRP-2 are described in PCT Patent PublicationWO 93/04081, and methods to obtain hexarelin are described in J.Endocrin. Invest., 15 (Suppl. 4), 45 (1992), all of which areincorporated herein by reference.

[0207] In addition, the present invention includes within its scope theuse of a pharmaceutical composition according to the present inventioncomprising, as an active ingredient, at least one compound of thepresent invention in association with a pharmaceutical vehicle, carrieror diluent.

[0208] It will be known to those skilled in the art that other compoundsmay be used in an effort to stimulate gastrointestinal motility (see R.Faghih et al., Drugs of the Future, 23(8): 861-872 (1998); R. Faghih etal., J. Med. Chem., 41:3402-3408 (1998); H. A. Kirst, Exp. Opin. Ther.Patents, 8(2): 111-120 (1998), which are incorporated herein byreference). Combinations of these therapeutic agents, some of which havebeen mentioned herein, with a compound of the present invention willbring additional complementary, and often synergistic properties toenhance the desirable properties of these various therapeutic agents.Other prokinetic therapeutic agents, which are therapeutic agents usefulfor increasing gastrointestinal motility, include, for example,cisapride monohydrate, metoclopramide, erythromycin, domperidone,ondansetron, tropisetron, mosapride and itopride.

[0209] In these combinations, the compound of the present invention andthe other therapeutic agent(s) may be independently present in the doseranges from 0.01 to 1 times the dose levels which are effective whenthese compounds are used singly.

[0210] Typically, the individual daily dosages for these combinationsmay range from about one-fifth of the minimally recommended clinicaldosages to the maximum recommended levels for the entities when they aregiven singly. These dose ranges may be adjusted on a unit basis asnecessary to permit divided daily dosage and, as noted above, the dosewill vary depending on the nature and severity of the disease, weight ofpatient, special diets and other factors.

[0211] These combinations may be formulated into pharmaceuticalcompositions as known in the art and as discussed herein. Since thepresent invention has an aspect that relates to treatment with acombination of active ingredients which may be administered separately,the invention also relates to combining separate pharmaceuticalcompositions in kit form. The kit comprises two separate pharmaceuticalcompositions: a compound of the present invention, a prodrug thereof ora pharmaceutically acceptable salt of said compound or said prodrug; anda second therapeutic agent as described herein. The kit comprises acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

[0212] An example of such a kit is a so-called blister pack. Blisterpacks are well known in the packaging industry and are being widely usedfor the packaging of pharmaceutical unit dosage forms (tablets,capsules, and the like). Blister packs generally consist of a sheet ofrelatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process, recesses areformed in the plastic foil. The recesses have the size and shape of thetablets or capsules to be packed. Next, the tablets or capsules areplaced in the recesses and the sheet of relatively stiff material issealed against the plastic foil at the face of the foil which isopposite from the direction in which the recesses were formed. As aresult, the tablets or capsules are sealed in the recesses between theplastic foil and the sheet. Preferably, the strength of the sheet issuch that the tablets or capsules can be removed from the blister packby manually applying pressure on the recesses whereby an opening isformed in the sheet at the place of the recess. The tablet or capsulecan then be removed via said opening.

[0213] It may be desirable to provide a memory aid on the kit, e g., inthe form of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the dosage form sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day. Also, a daily dose of a second therapeutic agentas describe herein can consist of one tablet or capsule while a dailydose of a compound of the present invention, a prodrug thereof orpharmaceutically acceptable salt of said compound or said prodrug canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

[0214] In another specific embodiment of the invention, a dispenserdesigned to dispense the daily doses one at a time in the order of theirintended use is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

[0215] The utility of the compounds described herein in the methods ofthe present invention are demonstrated by their activity in one or moreof the assays described below:

[0216] Assay for Stimulation of Growth Hormone Release from RatPituicytes

[0217] Compounds having the ability to stimulate GH secretion fromcultured rat pituitary cells are identified using the followingprotocol. This test is also useful for comparison to standards todetermine dosage levels.

[0218] Cells are isolated from pituitaries of 6-week old male Wistarrats. Following decapitation, the anterior pituitary lobes are removedinto cold, sterile Hank's balanced salt solution without calcium ormagnesium (HBSS). Tissues are finely minced, then subjected to twocycles of mechanically assisted enzymatic dispersion using 10 U/mLbacterial protease (EC 3.4.24.4, Sigma P-6141, St. Louis, Mo.) in HBSS.The tissue-enzyme mixture is stirred in a spinner flask at 30 rpm in a5% CO₂ atmosphere at 37° C. for 30 min., with manual trituration after15 min. and 30 min. using a 10-mL pipet. This mixture is centrifuged at200×g for 5 min. Horse serum (35% final concentration) is added to thesupernatant to neutralize excess protease. The pellet is resuspended infresh protease (10 U/mL), stirred for about 30 min. more under theprevious conditions, and manually triturated, ultimately through a23-gauge needle. Again, horse serum (35% final concentration) is added,then the cells from both digests are combined, pelleted (200×g for about15 min.), resuspended in culture medium (Dulbecco's Modified EagleMedium (D-MEM) supplemented with 4.5 g/L glucose, 10% horse serum, 2.5%fetal bovine serum, 1% non-essential amino acids, 100 U/mL nystatin and50 mg/mL gentamycin sulfate, Gibco, Grand Island, N.Y.) and counted.Cells are plated at 6.0-6.5×10⁴ cells per cm² in 48-well Costar™(Cambridge, Mass.) dishes and cultured for 3-4 days in culture medium.

[0219] Just prior to carrying out a GH secretion assay, culture wellsare rinsed twice with release medium, then equilibrated for 30 minutesin release medium (D-MEM buffered with 25 mM Hepes, pH 7.4 andcontaining 0.5% bovine serum albumin at 37° C.). Test compositions aredissolved in DMSO, then diluted into pre-warmed release medium. Assaysare typically run in quadruplicate. The assay is initiated by adding 0.5mL of release medium (with vehicle or test compound) to each culturewell. Incubation is carried out at 37° C. for 15 minutes, thenterminated by removal of the release medium, which is centrifuged at2000×g for 15 minutes to remove cellular material. Rat growth hormoneconcentrations in the supernatants are determined by a standardradioimmunoassay protocol described below.

Assay for Exogenously-Stimulated Growth Hormone Release in the Rat AfterIntravenous Administration of Test Compounds

[0220] Twenty-one day old female Sprague-Dawley rats (Charles RiverLaboratory, Wilmington, Mass.) are allowed to acclimate to localvivarium conditions (24° C., 12 hr light, 12 hr dark cycle) forapproximately 1 week before testing of a compound of this invention. Allrats are allowed access to water and a pelleted commercial diet (AgwayCountry Food, Syracuse N.Y.) ad libitum.

[0221] On the day of the experiment, test compounds are dissolved invehicle containing 1% ethanol, 1 mM acetic acid and 0.1% bovine serumalbumin in saline. Each test is conducted in three rats. Rats areweighed and anesthetized via intraperitoneal injection of sodiumpentobarbital (Nembutol®, 50 mg/kg body weight). Fourteen minutes afteranesthetic administration, a blood sample is taken by nicking the tip ofthe tail and allowing the blood to drip into a microcentrifuge tube(baseline blood sample, approximately 100 μl). Fifteen minutes afteranesthetic administration, a test compound is delivered by intravenousinjection into the tail vein, with a total injection volume of 1 mL/kgbody weight. Additional blood samples are taken from the tail at 5, 10and 15 minutes after administration of a compound of this invention.Blood samples are kept on ice until serum separation by centrifugation(1430×g for 10 minutes at 10° C.). Serum is stored at −80° C. untilserum growth hormone determination by radioimmunoassay as describedbelow.

Measurement of Rat Growth Hormone

[0222] Rat growth hormone concentrations are determined by doubleantibody radioimmunoassay using a rat growth hormone referencepreparation (NIDDK-rGH-RP-2) and rat growth hormone antiserum raised inmonkey (NIDDK-anti-rGH-S-5) obtained from Dr. A. Parlow (Harbor-UCLAMedical Center, Torrance, Calif.). Additional rat growth hormone (1.5U/mg, #G2414, Scripps Labs, San Diego, Calif.) is iodinated to aspecific activity of approximately 30 μCi/μg by the chloramine T methodfor use as tracer. Immune complexes are obtained by adding goatantiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) plus polyethyleneglycol, MW 10,000-20,000 to a final concentration of 4.3%; recovery isaccomplished by centrifugation according to methods well known to thoseskilled in the art. This assay has a working range of 0.08-2.5 μg ratgrowth hormone per tube.

Assessment of Growth Hormone Release in the Dog after OralAdministration

[0223] On the day of dosing, the test compound is weighed out for theappropriate dose and dissolved in water. Doses are delivered at a volumeof 0.5-3 mL/kg by oral gavage to 2-4 dogs for each dosing regimen. Bloodsamples (5 mL) are collected from the jugular vein by directvenipuncture pre-dose and at 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 and 24hours post dose using 5 mL vacutainers containing lithium heparin. Theprepared plasma is stored at −20° C. until analysis.

Measurement of Canine Growth Hormone

[0224] Canine growth hormone concentrations are determined by a standardradioimmunoassay protocol using canine growth hormone (antigen foriodination and reference preparation AFP-1983B) and canine growthhormone antiserum raised in monkey (AFP-21452578) obtained from Dr. A.Parlow (Harbor-UCLA Medical Center, Torrence, Calif.). Tracer isproduced by chloramine T-iodination of canine growth hormone to aspecific activity of 20-40 μCi/μg. Immune complexes are obtained byadding goat antiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) pluspolyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%;recovery is accomplished by centrifugation according to methods wellknown to those skilled in the art. This assay has a working range of0.08-2.5 μg canine GH/tube.

Assessment of Canine Growth Hormone and Insulin-Like Growth Factor-1Levels in the Dog after Chronic Oral Administration

[0225] The dogs receive test compound daily for either 7 or 14 days.Each day of dosing, the test compound is weighed out for the appropriatedose and dissolved in water. Doses are delivered at a volume of 0.5-3ml/kg by gavage to 5 dogs for each dosing regimen. Blood samples arecollected at days 0, 3, 7, 10 and 14. Blood samples (5 ml) are obtainedby direct venipuncture of the jugular vein at pre-dose, 0.17, 0.33, 0.5,0.75, 1, 2, 3, 6, 8, 12 and 24 hours post administration on days 0, 7and 14 using 5 ml vacutainers containing lithium heparin for GHdetermination. In addition, blood is drawn pre-dose and 8 hours afterdosing on days 3 and 10 for IGF-I determination. The prepared plasma isstored at −20° C. until analysis.

[0226] Plasma samples are extracted with acid ethanol (0.25N HCl in 90%ethanol), centrifuged, then the supernatant is neutralized withtris[hydroxymethyl]amino-methane (registered name is TRIZMA base,manufactured by Sigma Chemical Co.) prior to determination of IGF-Iconcentration using the Nichols Institute IGF-I extraction kit (San JuanCapistrano, Calif.).

Gastrointestinal Transit in Rats

[0227] Male CD Sprague-Dawley rats (175-225 grams) are fitted with tailcups to prevent coprophagy and fasted overnight. The next day the ratsare orally given either vehicle (water, 5 ml/kg) or a solution of thetest compound in water at doses of 0.1, 0.5, 1 or 5 mg/kg p.o. Fifteenminutes later, the rats are given 1.0 ml of an evaporated milk solutioncontaining 20,000 cpm of ⁵¹Cr as sodium chromate.

[0228] The rats are killed 20 minutes after administration of theradioactive marker. The gastroesophageal, pyloric, and ileocecaljunctions are ligated, the stomach is removed and the small intestine isdivided into ten equal lengths. The stomach and each length of intestineare assayed for radioactivity with a gamma counter. Gastric emptying isdetermined for each rat by comparing the amount of radioactivity in theintestine relative to the total in the intestine plus stomach. Inaddition, the geometric center of the distribution of the radioactivemarker is used to measure the overall transit rate through the stomachand intestine. Geometric center is calculated as: Σ((fraction of ⁵¹Crper segment)×(segment number)). For these calculations the stomach issegment number 0 while the ten intestinal segments are designated 1 to10. Thus, a geometric center of 0.0 would indicate that the entire loadof ⁵¹Cr had remained in the stomach.

[0229] Results from test compound-treated rats and vehicle-treated ratsare compared using one-way ANOVA and Dunnett's test for simultaneousmultiple comparisons. The effect of the test compound ongastrointestinal transit in rats is evaluated by measuring gastricemptying and the geometric center of distribution of an orallyadministered radioactive marker.

[0230] At a dose of 0.1 mg/kg, the first test compound,2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,had no effect on gastrointestinal transit. At doses of 0.5, 1.0, and 5.0mg/kg, the first test compound increased gastric emptying by 25%, 45%,and 49%, respectively (see Table 1 below). A level of gastric emptyinggreater than 90%, as was seen after the 1 mg/kg and 5 mg/kg doses (92%and 94%, respectively), is considered maximal. The increases ingeometric centers (a measure of transit through both the stomach andsmall intestine) were 39% at 0.5 mg/kg, 67% at 1 mg/kg and 68% at 5mg/kg. TABLE 1 Effect of Oral First Test Compound on GastrointestinalTransit in the Rat. A ⁵¹Cr-containing solution was administered to rats15 minutes after oral administration of the first test compound orwater. Twenty minutes later, the stomach and small intestine, dividedinto ten segments of equal length, were assayed for radioactivity.Gastric emptying = % of total ⁵¹Cr in the intestine; geometric center =Σ((fraction of ⁵¹Cr per segment) × (segment number)). Data shown aremean ± SEM. % Gastric Geometric Treatment N Emptying Center Vehicle(water) 15   63.0 ± 2.4  2.89 ± 0.13 1^(st) test compound 0.1 mg/kg 8 62.5 ± 3.4  2.82 ± 0.17 0.5 mg/kg 8 *79.0 ± 4.2 *4.03 ± 0.26 1 mg/kg 7*91.5 ± 1.6 *4.81 ± 0.21 5 mg/kg 7 *93.7 ± 1.4 *4.85 ± 0.19

[0231] An oral dose of 0.1 mg/kg of the second test compound,2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,had no effect on gastrointestinal transit. Doses of 0.5, 1, and 5 mg/kgincreased both gastric emptying and the transport through the upper GItract. At doses of 0.5, 1.0, and 5.0 mg/kg, the second test compoundincreased gastric emptying by 21%, 37%, and 34%, respectively (see Table2 below). The increases in geometric centers (a measure of transitthrough both the stomach and small intestine) were 37% at 0.5 mg/kg, 50%at 1 mg/kg and 42% at 5 mg/kg. TABLE 2 Effect of Oral Second TestCompound on Gastrointestinal Transit in the Rat. A ⁵¹Cr-containingsolution was administered to rats 15 minutes after oral administrationof the second test compound or water. Twenty minutes later, the stomachand small intestine, divided into ten segments of equal length, wereassayed for radioactivity. Gastric emptying = % of total ⁵¹Cr in theintestine; geometric center = Σ((fraction of ⁵¹Cr per segment) ×(segment number)). Data shown are mean ± SEM. % Gastric GeometricTreatment N Emptying Center Vehicle (water) 11  65.8 ± 4.1  2.9 ± 0.22^(nd) test compound 0.1 mg/kg  9  68.9 ± 3.0  3.1 ± 0.2 0.5 mg/kg 10*79.5 ± 3.6 *3.9 ± 0.3 1 mg/kg  9 *89.9 ± 2.3 *4.3 ± 0.2 5 mg/kg 11*88.3 ± 2.4 *4.1 ± 0.2

[0232] While the foregoing description discloses the present invention,with examples provided for the purpose of illustration, it will beunderstood that the practice of the present invention encompasses all ofthe usual variations, adaptations or modifications as come within thescope of the following claims and their equivalents.

1. A method of stimulating the motility of the gastrointestinal systemin a patient which comprises administering to the patient agastrointestinal motility stimulating effective amount of a growthhormone secretagogue.
 2. A method of claim 1 wherein the growth hormonesecretagogue is an orally active growth hormone secretagogue.
 3. Amethod of claim 2 wherein the growth hormone secretagogue is orallyadministered.
 4. A method of claim 1 wherein the growth hormonesecretagogue is a non-peptidyl growth hormone secretagogue.
 5. A methodof claim 1 wherein the patient is a human.
 6. A method of stimulatingthe motility of the gastrointestinal system in a patient which comprisesadministering to the patient a gastrointestinal motility stimulatingeffective amount of a compound of the Formula I:

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, or a tautomer thereof, wherein: HET is a heterocyclicmoiety selected from the group consisting of

d is 0, 1 or 2; e is 1 or 2; f is 0 or 1; n and w are 0, 1 or 2,provided that n and w cannot both be 0 at the same time; Y² is oxygen orsulfur; A is a divalent radical, where the left hand side of the radicalas shown below is connected to C″ and the right hand side of the radicalas shown below is connected to C′, selected from the group consisting of—NR²—C(O)—NR²—, —NR²—S(O)₂—NR², —O—C(O)—NR², —NR²—C(O)—O—,—C(O)—NR²—C(O)—, —C(O)—NR²—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—O—C(O)—, —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—, —NR²—C(O)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(O)—NR²—, —C(R⁹R¹⁰)—C(O)—O—,—C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—C(O)—,—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—, —C(R⁹R¹⁰)—NR²—C(O)—O—, —C(R⁹R¹⁰)—O—O—C(O)—NR²,—C(R⁹R¹⁰)—NR²—C(O)—NR²—, —NR²—C(O)—O—C(R⁹R¹⁰)—, —NR²—C(O)—NR²—C(R⁹R¹⁰)—,—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—, —O—C(O)—NR²—C(R⁹R¹⁰)—, C(O)—N═C(R¹¹)—NR²—,—C(O)—NR²—C(R¹¹)═N—, —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—,—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—NR²—C(R¹¹)═N—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,—C(R⁹R¹⁰)—NR¹²—N═C(R¹¹)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—, —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—; Q is a covalentbond or CH₂; W is CH or N; X is CR⁹R¹⁰, C═CH₂ or C═O; Y is CR⁹R¹⁰, O orNR²; Z is C═O, C═S or S(O)₂; G¹ is hydrogen, halo, hydroxy, nitro,amino, cyano, phenyl, carboxyl, —CONH₂, -(C₁-C₄)alkyl optionallyindependently substituted with one or more phenyl, one or more halogensor one or more hydroxy groups, -(C₁-C₄)alkoxy optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl,N,N-di-(C₁-C₄)alkylamino, -(C₂-C₆)alkenyl optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₂-C₆)alkynyl optionally independently substitutedwith one or more phenyl, one or more halogens or one or more hydroxygroups, -(C₃-C₆)cycloalkyl optionally independently substituted with oneor more (C₁-C₄)alkyl groups, one or more halogens or one or more hydroxygroups, -(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G²and G³ are each independently selected from the group consisting ofhydrogen, halo, hydroxy, -(C₁-C₄)alkyl optionally independentlysubstituted with one to three halo groups and -(C₁-C₄)alkoxy optionallyindependently substituted with one to three halo groups; R¹ is hydrogen,—CN, —(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)—or —OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q)group and (CH₂)_(t) group in the definition of R¹ are optionallyindependently substituted with hydroxy, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups; R^(1A) is selected fromthe group consisting of hydrogen, F, Cl, Br, I, (C₁-C₆)alkyl,phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl, thiazolyl(C₁-C₃)alkyl andthienyl(C₁-C₃)alkyl, provided that R^(1A) is not F, Cl, Br or I when aheteroatom is vicinal to C″; R² is hydrogen, (C₁-C₈)alkyl,-(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹ or A¹; where the alkylgroups and the cycloalkyl groups in the definition of R² are optionallysubstituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2 or 3independently selected halo groups; R³ is selected from the groupconsisting of A¹, (C₁-C₁₀)alkyl, -(C₁-C₆)alkyl-A¹,-(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, -(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ and-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independently selectedhalo groups or 1, 2 or 3 independently selected —OX³ groups; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are each independently 0, 1, 2 or 3; X⁵ and X^(5a) areeach independently selected from the group consisting of hydrogen, CF₃,A¹ and optionally substituted (C₁-C₆)alkyl; the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X^(5a) is optionallysubstituted with a substituent selected from the group consisting of A¹,OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX², (C₃-C₇)cycloalkyl, —N(X²)(X²) and—C(O)N(X²)(X²); or the carbon bearing X⁵ or X^(5a) forms one or twoalkylene bridges with the nitrogen atom bearing R⁷ and R⁸ wherein eachalkylene bridge contains 1 to 5 carbon atoms, provided that when onealkylene bridge is formed then only one of X⁵ or X^(5a) is on the carbonatom and only one of R⁷ or R⁸ is on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom; or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen; or X⁵ is takentogether with X^(5a) and the carbon atom to which they are attached andform a bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, optionally having 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O; or R⁶ is—(CR^(a)R^(b))_(a)—E—(CR^(a)R^(b))_(b)—, where the —(CR^(a)R^(b))_(a)group is attached to the carbonyl carbon of the amide group of thecompound of formula I and the —(CR^(a)R^(b))_(b) group is attached tothe terminal nitrogen atom of the compound of Formula I; E is —O—, —S—,—CH═CH— or an aromatic moiety selected from

said aromatic moiety in the definition of E optionally substituted withup to three halo, hydroxy, —N(R^(c))(R^(c)), (C₁-C₆)alkyl or(C₁-C₆)alkoxy; R^(a) and R^(b) are, for each occurrence, independentlyhydrogen, (C₁-C₆)alkyl, trifluoromethyl, phenyl or monosubstituted(C₁-C₆)alkyl where the substituents are imidazolyl, naphthyl, phenyl,indolyl, p-hydroxyphenyl, —OR^(c), S(O)_(m)R^(c), C(O)OR^(c),(C₃-C₇)cycloalkyl, —N(R^(c))(R^(c)), —C(O)N(R^(c))(R^(c)), or R^(a) orR^(b) may independently be joined to one or both of R⁷ or E (where E isother than O, S or —CH═CH—) to form an alkylene bridge between theterminal nitrogen and the alkyl portion of the R^(a) or R^(b) and the R⁷or E group, wherein the bridge contains 1 to 8 carbon atoms; or R^(a)and R^(b) may be joined to one another to form a (C₃-C₇)cycloalkyl;R^(c), for each occurrence, is independently hydrogen or (C₁-C₆)alkyl; aand b are independently 0, 1, 2 or 3, with the proviso that if E is —O—or —S—, b is other than 0 or 1 and with the further proviso that if E is—CH═CH—, b is other than 0; R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5halo groups, 1 to 3 hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groupsor 1 to 3 (C₁-C₆)alkoxy groups; or R⁷ and R⁸ can be taken together toform —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m) or N(X²);R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionally independentlysubstituted with 1-5 halo groups; R¹¹ is selected from the groupconsisting of (C₁-C₅)alkyl and phenyl optionally substituted with 1-3substituents each independently selected from the group consisting of(C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or I to3 (C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl,thiazolyl, imidazolyl, furyl or thienyl, provided that when X¹² is nothydrogen, the X¹² group is optionally substituted with one to threesubstituents independently selected from the group consisting of Cl, F,CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); r foreach occurrence is independently 1, 2 or 3; X² for each occurrence isindependently hydrogen, optionally substituted (C₁-C₆)alkyl oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or 1-3 OX³ groups;X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ foreach occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxy; m for each occurrence isindependently 0, 1 or 2; with the provisos that: 1) X⁶ and X¹² cannot behydrogen when attached to C(O) or S(O)₂ in the form C(O)X⁶, C(O)X¹²,S(O)₂X⁶ or S(O)₂X¹²; and 2) when R⁶ is a bond then L is N(X²) and each rin the definition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 7. Amethod of claim 6 wherein the compound is of the Formula I-A

a racemic-diastereomeric mixture or an optical isomer of said compoundor a pharmaceutically-acceptable salt or prodrug thereof, or a tautomerthereof, wherein f is 0; n is 0 and w is 2, or n is 1 and w is 1, or nis 2 and w is 0; Y is oxygen or sulfur; R¹ is hydrogen, —CN,—(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁸)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³ is A¹, (C₁-C₁₀)alkyl,-(C₁-C₆)alkyl-A¹, -(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, -(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with,—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen,(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴is taken together with R⁴ and the nitrogen atom to which X⁴ is attachedand the carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); R⁷ and R⁸ areindependently hydrogen or optionally substituted (C₁-C₆)alkyl; where theoptionally substituted (C₁-C₆)alkyl in the definition of R⁷ and R⁸ isoptionally independently substituted with A¹, —C(O)O—(C₁-C₆)alkyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3—O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or R⁷ and R⁸ can be takentogether to form —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m)or N(X²); A¹ in the definition of R¹ is a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen, a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, having 1 to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; A¹ inthe definition of R², R³, R⁶, R⁷ and R⁸ is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurrenceis independently optionally substituted, in one or optionally both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of F, Cl,Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹²,—NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl ortetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, the X¹² is optionally substituted withone to three substituents independently selected from the groupconsisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are takentogether to form —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O,S(O)_(m) or N(X²); r for each occurrence is independently 1, 2 or 3; X²for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;X⁶ is independently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)-halogenatedcycloalkyl, where optionally substituted (C₁-C₆)alkyland optionally substituted (C₃-C₇)cycloalkyl in the definition of X⁶ isoptionally independently substituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate(C₁-C₄)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X⁶ groupson one atom and both X⁶ are independently (C₁-C₆)alkyl, the two(C₁-C₆)alkyl groups may be optionally joined and, together with the atomto which the two X⁶ groups are attached, form a 4- to 9- membered ringoptionally having oxygen, sulfur or NX⁷; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxyl; and m for each occurrence isindependently 0, 1 or 2; with the proviso that: X⁶ and X¹² cannot behydrogen when it is attached to C(O) or SO₂ in the form C(O)X⁶, C(O)X¹²,SO₂X⁶ or SO₂X¹²; and when R⁶ is a bond then L is N(X²) and each r in thedefinition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 8. A methodof claim 7 wherein the compound is2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 9. A method of claim 8 wherein the compound is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,L-tartrate.
 10. A method of claim 7 wherein the compound is2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 11. A method of claim 10 wherein the compound is the(L)-(+)-tartaric acid salt of2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide.12. A method of claim 6 wherein the compound is2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 13. A method of claim 12 wherein the compound is the(L)-(+)-tartaric acid salt of2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.14. A method of claim 1 which further comprises administering aprokinetic agent.
 15. A method of claim 14 wherein the prokinetic agentis selected from the group consisting of cisapride monohydrate,metoclopramide, erythromycin, domperidone, ondansetron, tropisetron,mosapride and itopride.
 16. A method of claim 1 which further comprisesadministering a recombinant growth hormone or a growth hormonesecretagogue selected from the group consisting of GHRP-6, GHRP-1,GHRP-2, hexarelin, growth hormone releasing factor, an analog of growthhormone releasing factor, IGF-1 and IGF-II.
 17. A method of stimulatinggastrointestinal transit in a patient which comprises administering tothe patient a gastrointestinal transit stimulating effective amount of agrowth hormone secretagogue.
 18. The method of claim 17 wherein thegrowth hormone secretagogue is an orally active growth hormonesecretagogue.
 19. The method of claim 18 wherein the growth hormonesecretagogue is orally administered.
 20. A method of claim 17 whereinthe growth hormone secretagogue is a non-peptidyl growth hormonesecretagogue.
 21. A method of claim 17 wherein the patient is a human.22. A method of stimulating gastrointestinal transit in a patient whichcomprises administering to the patient a gastrointestinal transitstimulating effective amount of a compound of the Formula I:

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, or a tautomer thereof, wherein: HET is a heterocyclicmoiety selected from the group consisting of

d is 0, 1 or 2; e is 1 or 2; f is 0 or 1; n and w are 0, 1 or 2,provided that n and w cannot both be 0 at the same time; Y² is oxygen orsulfur; A is a divalent radical, where the left hand side of the radicalas shown below is connected to C″ and the right hand side of the radicalas shown below is connected to C′, selected from the group consisting of—NR²—C(O)—NR²—, —NR²—S(O)₂—NR², —O—C(O)—NR², —NR²—C(O)—O—,—C(O)—NR²—C(O)—, —C(O)—NR²—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—O—C(O)—, —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—, —NR²—C(O)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(O)—NR²—, —C(R⁹R¹⁰)—C(O)—O—,—C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—C(O)—,—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—, —C(R⁹R¹⁰)—NR²—C(O)—O—, —C(R⁹R¹⁰)—O—O—C(O)—NR²,—C(R⁹R¹⁰)—NR²—C(O)—NR²—, —NR²—C(O)—O—C(R⁹R¹⁰)—, —NR²—C(O)—NR²—C(R⁹R¹⁰)—,—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—, —O—C(O)—NR²—C(R⁹R¹⁰)—, C(O)—N═C(R¹¹)—NR²—,—C(O)—NR²—C(R¹¹)═N—, —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—,—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—NR²—C(R¹¹)═N—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,—C(R⁹R¹⁰)—NR¹²—N═C(R¹¹)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—, —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—; Q is a covalentbond or CH₂; W is CH or N; X is CR⁹R¹⁰, C═CH₂ or C═O; Y is CR⁹R¹⁰, O orNR²; Z is C═O, C═S or S(O)₂; G¹ is hydrogen, halo, hydroxy, nitro,amino, cyano, phenyl, carboxyl, —CONH₂, -(C₁-C₄)alkyl optionallyindependently substituted with one or more phenyl, one or more halogensor one or more hydroxy groups, -(C₁-C₄)alkoxy optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl,N,N-di-(C₁-C₄)alkylamino, -(C₂-C₆)alkenyl optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₂-C₆)alkynyl optionally independently substitutedwith one or more phenyl, one or more halogens or one or more hydroxygroups, -(C₃-C₆)cycloalkyl optionally independently substituted with oneor more (C₁-C₄)alkyl groups, one or more halogens or one or more hydroxygroups, -(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G²and G³ are each independently selected from the group consisting ofhydrogen, halo, hydroxy, -(C₁-C₄)alkyl optionally independentlysubstituted with one to three halo groups and -(C₁-C₄)alkoxy optionallyindependently substituted with one to three halo groups; R¹ is hydrogen,—CN, —(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)—or —OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q)group and (CH₂)_(t) group in the definition of R¹ are optionallyindependently substituted with hydroxy, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups; R^(1A) is selected fromthe group consisting of hydrogen, F, Cl, Br, I, (C₁-C₆)alkyl,phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl, thiazolyl(C₁-C₃)alkyl andthienyl(C₁-C₃)alkyl, provided that R^(1A) is not F, Cl, Br or I when aheteroatom is vicinal to C″; R² is hydrogen, (C₁-C₈)alkyl,-(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹ or A¹; where the alkylgroups and the cycloalkyl groups in the definition of R² are optionallysubstituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2 or 3independently selected halo groups; R³ is selected from the groupconsisting of A¹, (C₁-C₁₀)alkyl, -(C₁-C₆)alkyl-A¹,-(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, -(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ and-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independently selectedhalo groups or 1, 2 or 3 independently selected —OX³ groups; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are each independently 0, 1, 2 or 3; X⁵ and X^(5a) areeach independently selected from the group consisting of hydrogen, CF₃,A¹ and optionally substituted (C₁-C₆)alkyl; the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X^(5a) is optionallysubstituted with a substituent selected from the group consisting of A¹,OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX², (C₃-C₇)cycloalkyl, —N(X²)(X²) and—C(O)N(X²)(X²); or the carbon bearing X⁵ or X^(5a) forms one or twoalkylene bridges with the nitrogen atom bearing R⁷ and R⁸ wherein eachalkylene bridge contains 1 to 5 carbon atoms, provided that when onealkylene bridge is formed then only one of X⁵ or X^(5a) is on the carbonatom and only one of R⁷ or R⁸ is on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom; or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen; or X⁵ is takentogether with X^(5a) and the carbon atom to which they are attached andform a bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, optionally having 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O; or R⁶ is—(CR^(a)R^(b))_(a)—E—(CR^(a)R^(b))_(b)—, where the —(CR^(a)R^(b))_(a)group is attached to the carbonyl carbon of the amide group of thecompound of formula I and the —(CR^(a)R^(b))_(b) group is attached tothe terminal nitrogen atom of the compound of Formula I; E is —O—, —S—,—CH═CH— or an aromatic moiety selected from

said aromatic moiety in the definition of E optionally substituted withup to three halo, hydroxy, —N(R^(c))(R^(c)), (C₁-C₆)alkyl or(C₁-C₆)alkoxy; R^(a) and R^(b) are, for each occurrence, independentlyhydrogen, (C₁-C₆)alkyl, trifluoromethyl, phenyl or monosubstituted(C₁-C₆)alkyl where the substituents are imidazolyl, naphthyl, phenyl,indolyl, p-hydroxyphenyl, —OR^(c), S(O)_(m)R^(c), C(O)OR^(c),(C₃-C₇)cycloalkyl, —N(R^(c))(R^(c)), —C(O)N(R^(c))(R^(c)), or R^(a) orR^(b) may independently be joined to one or both of R⁷ or E (where E isother than O, S or —CH═CH—) to form an alkylene bridge between theterminal nitrogen and the alkyl portion of the R^(a) or R^(b) and the R⁷or E group, wherein the bridge contains 1 to 8 carbon atoms; or R^(a)and R^(b) may be joined to one another to form a (C₃-C₇)cycloalkyl;R^(c), for each occurrence, is independently hydrogen or (C₁-C₆)alkyl; aand b are independently 0, 1, 2 or 3, with the proviso that if E is —O—or —S—, b is other than 0 or 1 and with the further proviso that if E is—CH═CH—, b is other than 0; R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5halo groups, 1 to 3 hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groupsor 1 to 3 (C₁-C₆)alkoxy groups; or R⁷ and R⁸ can be taken together toform —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m) or N(X²);R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionally independentlysubstituted with 1-5 halo groups; R¹¹ is selected from the groupconsisting of (C₁-C₅)alkyl and phenyl optionally substituted with 1-3substituents each independently selected from the group consisting of(C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or I to3 (C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl,thiazolyl, imidazolyl, furyl or thienyl, provided that when X¹² is nothydrogen, the X¹² group is optionally substituted with one to threesubstituents independently selected from the group consisting of Cl, F,CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); r foreach occurrence is independently 1, 2 or 3; X² for each occurrence isindependently hydrogen, optionally substituted (C₁-C₆)alkyl oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or 1-3 OX³ groups;X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ foreach occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxy; m for each occurrence isindependently 0, 1 or 2; with the provisos that: 1) X⁶ and X¹² cannot behydrogen when attached to C(O) or S(O)₂ in the form C(O)X⁶, C(O)X¹²,S(O)₂X⁶ or S(O)₂X¹²; and 2) when R⁶ is a bond then L is N(X²) and each rin the definition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 23. Amethod of claim 22 wherein the compound is of the Formula I-A

a racemic-diastereomeric mixture or optical isomer of said compound or apharmaceutically-acceptable salt or prodrug thereof, or a tautomerthereof, wherein f is 0; n is 0 and w is 2, or n is 1 and w is 1, or nis 2 and w is 0; Y is oxygen or sulfur; R¹ is hydrogen, —CN,—(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁸)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³ is A¹, (C₁-C₁₀)alkyl,-(C₁-C₆)alkyl-A¹, -(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, -(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with,—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen,(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴is taken together with R⁴ and the nitrogen atom to which X⁴ is attachedand the carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); R⁷ and R⁸ areindependently hydrogen or optionally substituted (C₁-C₆)alkyl; where theoptionally substituted (C₁-C₆)alkyl in the definition of R⁷ and R⁸ isoptionally independently substituted with A¹, —C(O)O—(C₁-C₆)alkyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3—O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or R⁷ and R⁸ can be takentogether to form —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m)or N(X²); A¹ in the definition of R¹ is a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen, a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, having 1 to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; A¹ inthe definition of R², R³, R⁶, R⁷ and R⁸ is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurrenceis independently optionally substituted, in one or optionally both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of F, Cl,Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹²,—NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl ortetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, the X¹² is optionally substituted withone to three substituents independently selected from the groupconsisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are takentogether to form —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O,S(O)_(m) or N(X²); r for each occurrence is independently 1, 2 or 3; X²for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;X⁶ is independently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)-halogenatedcycloalkyl, where optionally substituted (C₁-C₆)alkyland optionally substituted (C₃-C₇)cycloalkyl in the definition of X⁶ isoptionally independently substituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate(C₁-C₄)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X⁶ groupson one atom and both X⁶ are independently (C₁-C₆)alkyl, the two(C₁-C₆)alkyl groups may be optionally joined and, together with the atomto which the two X⁶ groups are attached, form a 4- to 9- membered ringoptionally having oxygen, sulfur or NX⁷; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxyl; and m for each occurrence isindependently 0, 1 or 2; with the proviso that: X⁶ and X¹² cannot behydrogen when it is attached to C(O) or SO₂ in the form C(O)X⁶, C(O)X¹²,SO₂X⁶ or SO₂X¹²; and when R⁶ is a bond then L is N(X²) and each r in thedefinition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 24. A methodof claim 23 wherein the compound is2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 25. A method of claim 24 wherein the compound is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,L-tartrate.
 26. A method of claim 23 wherein the compound is2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 27. A method of claim 26 wherein the compound is the(L)-(+)-tartaric acid salt of2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide.28. A method of claim 22 wherein the compound is2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 29. A method of claim 28 wherein the compound is the(L)-(+)-tartaric acid salt of2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.30. A method of claim 17 which further comprises administering aprokinetic agent.
 31. A method of claim 30 wherein the prokinetic agentis selected from the group consisting of cisapride monohydrate,metoclopramide, erythromycin, domperidone, ondansetron, tropisetron,mosapride and itopride.
 32. A method of claim 17 which further comprisesadministering a recombinant growth hormone or a growth hormonesecretagogue selected from the group consisting of GHRP-6, GHRP-1,GHRP-2, hexarelin, growth hormone releasing factor, an analog of growthhormone releasing factor, IGF-I and IGF-II.
 33. A method for treating acondition selected from the group consisting of gastroesophageal refluxdisease, gastroparesis, postoperative ileus, emesis, constipation andcolonic pseudo-obstruction in a patient which comprises administering tothe patient a condition treating effective amount of a growth hormonesecretagogue.
 34. A method of claim 33 wherein the condition isgastroesophageal reflux disease, gastroparesis, postoperative ileus oremesis.
 35. A method of claim 33 wherein the growth hormone secretagogueis an orally active growth hormone secretagogue.
 36. A method of claim35 wherein the growth hormone secretagogue is orally administered.
 37. Amethod of claim 33 wherein the growth hormone secretagogue is anon-peptidyl growth hormone secretagogue.
 38. A method of claim 33wherein the patient is a human.
 39. A method for treating a conditionselected from the group consisting of gastroesophageal reflux disease,gastroparesis, postoperative ileus, emesis, constipation and colonicpseudo-obstruction in a patient which comprises administering to thepatient a condition treating effective amount of a compound of theFormula I:

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, or a tautomer thereof, wherein: HET is a heterocyclicmoiety selected from the group consisting of R¹¹ is selected from thegroup consisting of (C₁-C₅)alkyl and phenyl optionally substituted with1-3 substituents each independently selected from the group consistingof (C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or I to3 (C₁-C₆)alkoxy groups; —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—, —C(R⁹R¹⁰)—NR²—C(O)—O—,—C(R⁹R¹⁰)—O—O—C(O)—NR², —C(R⁹R¹⁰)—NR²—C(O)—NR²—, —NR²—C(O)—O—C(R⁹R¹⁰)—,—NR²—C(O)—NR²—C(R⁹R¹⁰)—, —NR²—S(O)₂—NR²—C(R⁹R¹⁰)—,—O—C(O)—NR²—C(R⁹R¹⁰)—, C(O)—N═C(R¹¹)—NR²—, —C(O)—NR²—C(R¹¹)═N—,—C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —NR²—C(R¹¹)═N—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—, —C(R⁹R¹⁰)—NR¹²—N═C(R¹¹)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—, —C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—, —O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—,—C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—, —C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and—C(R⁹R¹⁰)—NR²—S(O)₂—NR²—; Q is a covalent bond or CH₂; W is CH or N; Xis CR⁹R¹⁰, C═CH₂ or C═O; Y is CR⁹R¹⁰, O or NR²; Z is C═O, C═S or S(O)₂;G¹ is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl, carboxyl,—CONH₂, -(C₁-C₄)alkyl optionally independently substituted with one ormore phenyl, one or more halogens or one or more hydroxy groups,-(C₁-C₄)alkoxy optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,-(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl, N,N-di-(C₁-C₄)alkylamino,-(C₂-C₆)alkenyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,-(C₂-C₆)alkynyl optionally independently substituted with one or morephenyl, one or more halogens or one or more hydroxy groups,-(C₃-C₆)cycloalkyl optionally independently substituted with one or more(C₁-C₄)alkyl groups, one or more halogens or one or more hydroxy groups,-(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G² and G³are each independently selected from the group consisting of hydrogen,halo, hydroxy, -(C₁-C₄)alkyl optionally independently substituted withone to three halo groups and -(C₁-C₄)alkoxy optionally independentlysubstituted with one to three halo groups; R¹ is hydrogen, —CN,—(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)—or —OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q)group and (CH₂)_(t) group in the definition of R¹ are optionallyindependently substituted with hydroxy, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups; R^(1A) is selected fromthe group consisting of hydrogen, F, Cl, Br, I, (C₁-C₆)alkyl,phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl, thiazolyl(C₁-C₃)alkyl andthienyl(C₁-C₃)alkyl, provided that R^(1A) is not F, Cl, Br or I when aheteroatom is vicinal to C″; R² is hydrogen, (C₁-C₈)alkyl,-(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹ or A¹; where the alkylgroups and the cycloalkyl groups in the definition of R² are optionallysubstituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2 or 3independently selected halo groups; R³ is selected from the groupconsisting of A¹, (C₁-C₁₀)alkyl, -(C₁-C₆)alkyl-A¹,-(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, -(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ and-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independently selectedhalo groups or 1, 2 or 3 independently selected —OX³ groups; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are each independently 0, 1, 2 or 3; X⁵ and X^(5a) areeach independently selected from the group consisting of hydrogen, CF₃,A¹ and optionally substituted (C₁-C₆)alkyl; the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X^(5a) is optionallysubstituted with a substituent selected from the group consisting of A¹,OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX², (C₃-C₇)cycloalkyl, —N(X²)(X²) and—C(O)N(X²)(X²); or the carbon bearing X⁵ or X^(5a) forms one or twoalkylene bridges with the nitrogen atom bearing R⁷ and R⁸ wherein eachalkylene bridge contains 1 to 5 carbon atoms, provided that when onealkylene bridge is formed then only one of X⁵ or X^(5a) is on the carbonatom and only one of R⁷ or R⁸ is on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom; or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen; or X⁵ is takentogether with X^(5a) and the carbon atom to which they are attached andform a bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, optionally having 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O; or R⁶ is—(CR^(a)R^(b))_(a)—E—(CR^(a)R^(b))_(b)—, where the —(CR^(a)R^(b))_(a)group is attached to the carbonyl carbon of the amide group of thecompound of formula I and the —(CR^(a)R^(b))_(b) group is attached tothe terminal nitrogen atom of the compound of Formula I; E is —O—, —S—,—CH═CH— or an aromatic moiety selected from

said aromatic moiety in the definition of E optionally substituted withup to three halo, hydroxy, —N(R^(c))(R^(c)), (C₁-C₆)alkyl or(C₁-C₆)alkoxy; R^(a) and R^(b) are, for each occurrence, independentlyhydrogen, (C₁-C₆)alkyl, trifluoromethyl, phenyl or monosubstituted(C₁-C₆)alkyl where the substituents are imidazolyl, naphthyl, phenyl,indolyl, p-hydroxyphenyl, —OR^(c), S(O)_(m)R^(c), C(O)OR^(c),(C₃-C₇)cycloalkyl, —N(R^(c))(R^(c)), —C(O)N(R^(c))(R^(c)), or R^(a) orR^(b) may independently be joined to one or both of R⁷ or E (where E isother than O, S or —CH═CH—) to form an alkylene bridge between theterminal nitrogen and the alkyl portion of the R^(a) or R^(b) and the R⁷or E group, wherein the bridge contains 1 to 8 carbon atoms; or R^(a)and R^(b) may be joined to one another to form a (C₃-C₇)cycloalkyl;R^(c), for each occurrence, is independently hydrogen or (C₁-C₆)alkyl; aand b are independently 0, 1, 2 or 3, with the proviso that if E is —O—or —S—, b is other than 0 or 1 and with the further proviso that if E is—CH═CH—, b is other than 0; R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5halo groups, 1 to 3 hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groupsor 1 to 3 (C₁-C₆)alkoxy groups; or R⁷ and R⁸ can be taken together toform —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m) or N(X²);R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionally independentlysubstituted with 1-5 halo groups; R¹¹ is selected from the groupconsisting of (C₁-C₅)alkyl and phenyl optionally substituted with 1-3substituents each independently selected from the group consisting of(C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or I to3 (C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl,thiazolyl, imidazolyl, furyl or thienyl, provided that when X¹² is nothydrogen, the X¹² group is optionally substituted with one to threesubstituents independently selected from the group consisting of Cl, F,CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); r foreach occurrence is independently 1, 2 or 3; X² for each occurrence isindependently hydrogen, optionally substituted (C₁-C₆)alkyl oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or 1-3 OX³ groups;X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ foreach occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxy; m for each occurrence isindependently 0, 1 or 2; with the provisos that: 1) X⁶ and X¹² cannot behydrogen when attached to C(O) or S(O)₂ in the form C(O)X⁶, C(O)X¹²,S(O)₂X⁶ or S(O)₂X¹²; and 2) when R⁶ is a bond then L is N(X²) and each rin the definition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 40. Amethod of claim 39 wherein the compound is of the Formula I-A

a racemic-diastereomeric mixture or an optical isomer of said compoundor a pharmaceutically-acceptable salt or prodrug thereof, or a tautomerthereof wherein f is 0; n is 0 and w is 2, or n is 1 and w is 1, or n is2 and w is 0; Y is oxygen or sulfur; R¹ is hydrogen, —CN,—(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y¹ is O, S(O)_(m), —C(O)NX⁶—,—CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)— or—OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q) groupand (CH₂)_(t) group may each be optionally substituted with hydroxyl,(C₁-C₄)alkoxy, carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkylester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C₁-C₄)alkyl; R² ishydrogen, (C₁-C₈)alkyl, -(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl,-(C₁-C₄)alkyl-A¹ or A¹; where the alkyl groups and the cycloalkyl groupsin the definition of R² are optionally substituted with hydroxyl,—C(O)OX⁶, —C(O)N(X⁸)(X⁶), —N(X⁶)(X⁶), —S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹,—C(O)(X⁶), CF₃, CN or 1, 2 or 3 halogen; R³ is A¹, (C₁-C₁₀)alkyl,-(C₁-C₆)alkyl-A¹, -(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl, -(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ or-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with,—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3OX³; X¹ is O, S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—,—CX²═CX²—, —N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen,(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴is taken together with R⁴ and the nitrogen atom to which X⁴ is attachedand the carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are independently 0, 1, 2 or 3; X⁵ and X^(5a) are eachindependently selected from the group consisting of hydrogen,trifluoromethyl, A¹ and optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl in the definition of X⁵ and X^(5a)is optionally substituted with a substituent selected from the groupconsisting of A¹, OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX²,(C₃-C₇)cycloalkyl, —N(X²)(X²) and —C(O)N(X²)(X²); R⁷ and R⁸ areindependently hydrogen or optionally substituted (C₁-C₆)alkyl; where theoptionally substituted (C₁-C₆)alkyl in the definition of R⁷ and R⁸ isoptionally independently substituted with A¹, —C(O)O—(C₁-C₆)alkyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3—O—C(O)(C₁-C₁₀)alkyl or 1 to 3 (C₁-C₆)alkoxy; or R⁷ and R⁸ can be takentogether to form —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m)or N(X²); A¹ in the definition of R¹ is a partially saturated, fullysaturated or fully unsaturated 4- to 8-membered ring optionally having 1to 4 heteroatoms independently selected from the group consisting ofoxygen, sulfur and nitrogen, a bicyclic ring system consisting of apartially saturated, fully unsaturated or fully saturated 5- or6-membered ring, having 1 to 4 heteroatoms independently selected fromthe group consisting of nitrogen, sulfur and oxygen, fused to apartially saturated, fully saturated or fully unsaturated 5- or6-membered ring, optionally having 1 to 4 heteroatoms independentlyselected from the group consisting of nitrogen, sulfur and oxygen; A¹ inthe definition of R², R³, R⁶, R⁷ and R⁸ is independently(C₅-C₇)cycloalkenyl, phenyl or a partially saturated, fully saturated orfully unsaturated 4- to 8-membered ring optionally having 1 to 4heteroatoms independently selected from the group consisting of oxygen,sulfur and nitrogen, a bicyclic ring system consisting of a partiallysaturated, fully unsaturated or fully saturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen, fused to a partiallysaturated, fully saturated or fully unsaturated 5- or 6- membered ring,optionally having 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, sulfur and oxygen; A¹ for each occurrenceis independently optionally substituted, in one or optionally both ringsif A¹ is a bicyclic ring system, with up to three substituents, eachsubstituent independently selected from the group consisting of F, Cl,Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶, —C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo,(C₁-C₆)alkyl, nitro, cyano, benzyl, —S(O)_(m)(C₁-C₆)alkyl,1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl,methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶), —SO₂N(X⁶)(X⁶),—N(X⁶)SO₂-phenyl, —N(X⁶)SO₂X⁶, —CONX¹¹X¹², —SO₂NX¹¹X¹², —NX⁶SO₂X¹²,—NX⁶CONX¹¹X¹², —NX⁶SO₂NX¹¹X¹², —NX⁶C(O)X¹², imidazolyl, thiazolyl ortetrazolyl, provided that if A¹ is optionally substituted withmethylenedioxy then it can only be substituted with one methylenedioxy;where X¹¹ is hydrogen or optionally substituted (C₁-C₆)alkyl; theoptionally substituted (C₁-C₆)alkyl defined for X¹¹ is optionallyindependently substituted with phenyl, phenoxy, (C₁-C₆)alkoxycarbonyl,—S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3(C₁-C₁₀)alkanoyloxy or 1 to 3 (C₁-C₆)alkoxy; X¹² is hydrogen,(C₁-C₆)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, providedthat when X¹² is not hydrogen, the X¹² is optionally substituted withone to three substituents independently selected from the groupconsisting of Cl, F, CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are takentogether to form —(CH₂)_(r)—L¹—(CH₂)_(r)—; where L¹ is C(X²)(X²), O,S(O)_(m) or N(X²); r for each occurrence is independently 1, 2 or 3; X²for each occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, or optionally substituted (C₃-C₇)cycloalkyl, where theoptionally substituted (C₁-C₆)alkyl and optionally substituted(C₃-C₇)cycloalkyl in the definition of X² are optionally independentlysubstituted with —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halogens or 1-3OX³; X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl;X⁶ is independently hydrogen, optionally substituted (C₁-C₆)alkyl,(C₂-C₆)halogenated alkyl, optionally substituted (C₃-C₇)cycloalkyl,(C₃-C₇)-halogenatedcycloalkyl, where optionally substituted (C₁-C₆)alkyland optionally substituted (C₃-C₇)cycloalkyl in the definition of X⁶ isoptionally independently substituted by 1 or 2 (C₁-C₄)alkyl, hydroxyl,(C₁-C₄)alkoxy, carboxyl, CONH₂, —S(O)_(m)(C₁-C₆)alkyl, carboxylate(C₁-C₄)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X⁶ groupson one atom and both X⁶ are independently (C₁-C₆)alkyl, the two(C₁-C₆)alkyl groups may be optionally joined and, together with the atomto which the two X⁶ groups are attached, form a 4- to 9- membered ringoptionally having oxygen, sulfur or NX⁷; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxyl; and m for each occurrence isindependently 0, 1 or 2; with the proviso that: X⁶ and X¹² cannot behydrogen when it is attached to C(O) or SO₂ in the form C(O)X⁶, C(O)X¹²,SO₂X⁶ or SO₂X¹²; and when R⁶ is a bond then L is N(X²) and each r in thedefinition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or
 3. 41. A methodof claim 40 wherein the compound is2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 42. A method of claim 41 wherein the compound is2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide,L-tartrate.
 43. A method of claim 40 wherein the compound is2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 44. A method of claim 43 wherein the compound is the(L)-(+)-tartaric acid salt of2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide.45. A method of claim 39 wherein the compound is2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide,a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.
 46. A method of claim 45 wherein the compound is the(L)-(+)-tartaric acid salt of2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.47. A method of claim 33 which further comprises administering aprokinetic agent.
 48. A method of claim 47 wherein the prokinetic agentis selected from the group consisting of cisapride monohydrate,metoclopramide, erythromycin, domperidone, ondansetron, tropisetron,mosapride and itopride.
 49. A method of claim 33 which further comprisesadministering a recombinant growth hormone or an additional growthhormone secretagogue selected from the group consisting of GHRP-6,GHRP-1, GHRP-2, hexarelin, growth hormone releasing factor, an analog ofgrowth hormone releasing factor, IGF-I and IGF-II.
 50. A pharmaceuticalcomposition comprising a compound of Formula I

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, or a tautomer thereof, wherein: HET is a heterocyclicmoiety selected from the group consisting of

d is 0, 1 or 2; e is 1 or 2; f is 0 or 1; n and w are 0, 1 or 2,provided that n and w cannot both be 0 at the same time; Y² is oxygen orsulfur; A is a divalent radical, where the left hand side of the radicalas shown below is connected to C″ and the right hand side of the radicalas shown below is connected to C′, selected from the group consisting of—NR²—C(O)—NR²—, —NR²—S(O)₂—NR², —O—C(O)—NR², —NR²—C(O)—O—,—C(O)—NR²—C(O)—, —C(O)—NR²—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—O—C(O)—, —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—, —NR²—C(O)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(O)—NR²—, —C(R⁹R¹⁰)—C(O)—O—,—C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—C(O)—,—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—, —C(R⁹R¹⁰)—NR²—C(O)—O—, —C(R⁹R¹⁰)—O—O—C(O)—NR²,—C(R⁹R¹⁰)—NR²—C(O)—NR²—, —NR²—C(O)—O—C(R⁹R¹⁰)—, —NR²—C(O)—NR²—C(R⁹R¹⁰)—,—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—, —O—C(O)—NR²—C(R⁹R¹⁰)—, C(O)—N═C(R¹¹)—NR²—,—C(O)—NR²—C(R¹¹)═N—, —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—,—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—NR²—C(R¹¹)═N—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,—C(R⁹R¹⁰)—NR¹²—N═C(R¹¹)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—, —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—; Q is a covalentbond or CH₂; W is CH or N; X is CR⁹R¹⁰, C═CH₂ or C═O; Y is CR⁹R¹⁰, O orNR²; Z is C═O, C═S or S(O)₂; G¹ is hydrogen, halo, hydroxy, nitro,amino, cyano, phenyl, carboxyl, —CONH₂, -(C₁-C₄)alkyl optionallyindependently substituted with one or more phenyl, one or more halogensor one or more hydroxy groups, -(C₁-C₄)alkoxy optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl,N,N-di-(C₁-C₄)alkylamino, -(C₂-C₆)alkenyl optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₂-C₆)alkynyl optionally independently substitutedwith one or more phenyl, one or more halogens or one or more hydroxygroups, -(C₃-C₆)cycloalkyl optionally independently substituted with oneor more (C₁-C₄)alkyl groups, one or more halogens or one or more hydroxygroups, -(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G²and G³ are each independently selected from the group consisting ofhydrogen, halo, hydroxy, -(C₁-C₄)alkyl optionally independentlysubstituted with one to three halo groups and -(C₁-C₄)alkoxy optionallyindependently substituted with one to three halo groups; R¹ is hydrogen,—CN, —(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)—or —OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q)group and (CH₂)_(t) group in the definition of R¹ are optionallyindependently substituted with hydroxy, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups; R^(1A) is selected fromthe group consisting of hydrogen, F, Cl, Br, I, (C₁-C₆)alkyl,phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl, thiazolyl(C₁-C₃)alkyl andthienyl(C₁-C₃)alkyl, provided that R^(1A) is not F, Cl, Br or I when aheteroatom is vicinal to C″; R² is hydrogen, (C₁-C₈)alkyl,-(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹ or A¹; where the alkylgroups and the cycloalkyl groups in the definition of R² are optionallysubstituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2 or 3independently selected halo groups; R³ is selected from the groupconsisting of A¹, (C₁-C₁₀)alkyl, -(C₁-C₆)alkyl-A¹,-(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, -(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ and-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independently selectedhalo groups or 1, 2 or 3 independently selected —OX³ groups; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are each independently 0, 1, 2 or 3; X⁵ and X^(5a) areeach independently selected from the group consisting of hydrogen, CF₃,A¹ and optionally substituted (C₁-C₆)alkyl; the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X^(5a) is optionallysubstituted with a substituent selected from the group consisting of A¹,OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX², (C₃-C₇)cycloalkyl, —N(X²)(X²) and—C(O)N(X²)(X²); or the carbon bearing X⁵ or X^(5a) forms one or twoalkylene bridges with the nitrogen atom bearing R⁷ and R⁸ wherein eachalkylene bridge contains 1 to 5 carbon atoms, provided that when onealkylene bridge is formed then only one of X⁵ or X^(5a) is on the carbonatom and only one of R⁷ or R⁸ is on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom; or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen; or X⁵ is takentogether with X^(5a) and the carbon atom to which they are attached andform a bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, optionally having 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O; or R⁶ is—(CR^(a)R^(b))_(a)—E—(CR^(a)R^(b))_(b)—, where the —(CR^(a)R^(b))_(a)group is attached to the carbonyl carbon of the amide group of thecompound of formula I and the —(CR^(a)R^(b))_(b) group is attached tothe terminal nitrogen atom of the compound of Formula I; E is —O—, —S—,—CH═CH— or an aromatic moiety selected from

said aromatic moiety in the definition of E optionally substituted withup to three halo, hydroxy, —N(R^(c))(R^(c)), (C₁-C₆)alkyl or(C₁-C₆)alkoxy; R^(a) and R^(b) are, for each occurrence, independentlyhydrogen, (C₁-C₆)alkyl, trifluoromethyl, phenyl or monosubstituted(C₁-C₆)alkyl where the substituents are imidazolyl, naphthyl, phenyl,indolyl, p-hydroxyphenyl, —OR^(c), S(O)_(m)R^(c), C(O)OR^(c),(C₃-C₇)cycloalkyl, —N(R^(c))(R^(c)), —C(O)N(R^(c))(R^(c)), or R^(a) orR^(b) may independently be joined to one or both of R⁷ or E (where E isother than O, S or —CH═CH—) to form an alkylene bridge between theterminal nitrogen and the alkyl portion of the R^(a) or R^(b) and the R⁷or E group, wherein the bridge contains 1 to 8 carbon atoms; or R^(a)and R^(b) may be joined to one another to form a (C₃-C₇)cycloalkyl;R^(c), for each occurrence, is independently hydrogen or (C₁-C₆)alkyl; aand b are independently 0, 1, 2 or 3, with the proviso that if E is —O—or —S—, b is other than 0 or 1 and with the further proviso that if E is—CH═CH—, b is other than 0; R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5halo groups, 1 to 3 hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groupsor 1 to 3 (C₁-C₆)alkoxy groups; or R⁷ and R⁸ can be taken together toform —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m) or N(X²);R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionally independentlysubstituted with 1-5 halo groups; R¹¹ is selected from the groupconsisting of (C₁-C₅)alkyl and phenyl optionally substituted with 1-3substituents each independently selected from the group consisting of(C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or I to3 (C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl,thiazolyl, imidazolyl, furyl or thienyl, provided that when X¹² is nothydrogen, the X¹² group is optionally substituted with one to threesubstituents independently selected from the group consisting of Cl, F,CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); r foreach occurrence is independently 1, 2 or 3; X² for each occurrence isindependently hydrogen, optionally substituted (C₁-C₆)alkyl oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or 1-3 OX³ groups;X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ foreach occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxy; m for each occurrence isindependently 0, 1 or 2; with the provisos that: 1) X⁶ and X¹² cannot behydrogen when attached to C(O) or S(O)₂ in the form C(O)X⁶, C(O)X¹²,S(O)₂X⁶ or S(O)₂X¹²; and 2) when R⁶ is a bond then L is N(X²) and each rin the definition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3; andan additional compound useful to treat a condition selected from thegroup consisting of gastroesophageal reflux disease, gastroparesis,postoperative ileus, emesis, constipation and colonicpseudo-obstruction.
 51. A composition of claim 50 wherein the conditionis gastroesophageal reflux disease, gastroparesis, postoperative ileusor emesis.
 52. A composition of claim 50 wherein the additional compoundis a prokinetic agent.
 53. A composition of claim 52 wherein theprokinetic agent is selected from the group consisting of cisapridemonohydrate, metoclopramide, erythromycin, domperidone, ondansetron,tropisetron, mosapride and itopride.
 54. A kit for treating a conditionselected from the group consisting of gastroesophageal reflux disease,gastroparesis, postoperative ileus, emesis, constipation and colonicpseudo-obstruction, the kit comprising: a) a first pharmaceuticalcomposition comprising a compound of Formula I

or a stereoisomeric mixture thereof, diastereomerically enriched,diastereomerically pure, enantiomerically enriched or enantiomericallypure isomer thereof, or a prodrug of such compound, mixture or isomerthereof, or a pharmaceutically acceptable salt of the compound, mixture,isomer or prodrug, or a tautomer thereof, wherein: HET is a heterocyclicmoiety selected from the group consisting of

d is 0, 1 or 2; e is 1 or 2; f is 0 or 1; n and w are 0, 1 or 2,provided that n and w cannot both be 0 at the same time; Y² is oxygen orsulfur; A is a divalent radical, where the left hand side of the radicalas shown below is connected to C″ and the right hand side of the radicalas shown below is connected to C′, selected from the group consisting of—NR²—C(O)—NR²—, —NR²—S(O)₂—NR², —O—C(O)—NR², —NR²—C(O)—O—,—C(O)—NR²—C(O)—, —C(O)—NR²—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—NR²—C(O)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—O—C(O)—, —C(R⁹R¹⁰)—O—C(R⁹R¹⁰)—, —NR²—C(O)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(O)—NR²—, —C(R⁹R¹⁰)—C(O)—O—,—C(O)—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —S(O)₂—NR²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—C(O)—,—NR²—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —NR²—S(O)₂—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—O—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—NR²—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—, —C(R⁹R¹⁰)—NR²—C(O)—O—, —C(R⁹R¹⁰)—O—O—C(O)—NR²,—C(R⁹R¹⁰)—NR²—C(O)—NR²—, —NR²—C(O)—O—C(R⁹R¹⁰)—, —NR²—C(O)—NR²—C(R⁹R¹⁰)—,—NR²—S(O)₂—NR²—C(R⁹R¹⁰)—, —O—C(O)—NR²—C(R⁹R¹⁰)—, C(O)—N═C(R¹¹)—NR²—,—C(O)—NR²—C(R¹¹)═N—, —C(R⁹R¹⁰)—NR¹²—C(R⁹R¹⁰)—, —NR¹²—C(R⁹R¹⁰)—,—NR¹²—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(O)—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—,—NR²—C(R¹¹)═N—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—N(R¹²)—,—C(R⁹R¹⁰)—NR¹²—N═C(R¹¹)—NR²—C(O)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—NR²—S(O)₂—,—C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—NR²—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—C(O)—O—,—C(R⁹R¹⁰)—S(O)₂—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰)—S(O)₂—,—O—C(R⁹R¹⁰)—C(R⁹R¹⁰)—, —C(R⁹R¹⁰)—C(R⁹R¹⁰O—O—, —C(R⁹R¹⁰)—C(O)—C(R⁹R¹⁰)—,—C(O)—C(R⁹R¹⁰)—C(R⁹R¹⁰)— and —C(R⁹R¹⁰)—NR²—S(O)₂—NR²—; Q is a covalentbond or CH₂; W is CH or N; X is CR⁹R¹⁰, C═CH₂ or C═O; Y is CR⁹R¹⁰, O orNR²; Z is C═O, C═S or S(O)₂; G¹ is hydrogen, halo, hydroxy, nitro,amino, cyano, phenyl, carboxyl, —CONH₂, -(C₁-C₄)alkyl optionallyindependently substituted with one or more phenyl, one or more halogensor one or more hydroxy groups, -(C₁-C₄)alkoxy optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₁-C₄)alkylthio, phenoxy, —COO(C₁-C₄)alkyl,N,N-di-(C₁-C₄)alkylamino, -(C₂-C₆)alkenyl optionally independentlysubstituted with one or more phenyl, one or more halogens or one or morehydroxy groups, -(C₂-C₆)alkynyl optionally independently substitutedwith one or more phenyl, one or more halogens or one or more hydroxygroups, -(C₃-C₆)cycloalkyl optionally independently substituted with oneor more (C₁-C₄)alkyl groups, one or more halogens or one or more hydroxygroups, -(C₁-C₄)alkylamino carbonyl or di-(C₁-C₄)alkylamino carbonyl; G²and G³ are each independently selected from the group consisting ofhydrogen, halo, hydroxy, -(C₁-C₄)alkyl optionally independentlysubstituted with one to three halo groups and -(C₁-C₄)alkoxy optionallyindependently substituted with one to three halo groups; R¹ is hydrogen,—CN, —(CH₂)_(q)N(X⁶)C(O)X⁶, —(CH₂)_(q)N(X⁶)C(O)(CH₂)_(t)—A¹,—(CH₂)_(q)N(X⁶)S(O)₂(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)S(O)₂X⁶,—(CH₂)_(q)N(X⁶)C(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)N(X⁶)(X⁶), —(CH₂)_(q)C(O)N(X⁶)(CH₂)_(t)A¹,—(CH₂)_(q)C(O)OX⁶, —(CH₂)_(q)C(O)O(CH₂)_(t)—A¹, —(CH₂)_(q)OX⁶,—(CH₂)_(q)OC(O)X⁶, —(CH₂)_(q)OC(O)(CH₂)_(t)—A¹,—(CH₂)_(q)OC(O)N(X⁶)(CH₂)_(t)—A¹, —(CH₂)_(q)OC(O)N(X⁶)(X⁶),—(CH₂)_(q)C(O)X⁶, —(CH₂)_(q)C(O)(CH₂)_(t)—A¹, —(CH₂)_(q)N(X⁶)C(O)OX⁶,—(CH₂)_(q)N(X⁶)S(O)₂N(X⁶)(X⁶), —(CH₂)_(q)S(O)X⁶,—(CH₂)_(q)S(O)_(m)(CH₂)_(t)—A¹, -(C₁-C₁₀)alkyl, —(CH₂)_(t)—A¹,—(CH₂)_(q)-(C₃-C₇)cycloalkyl, —(CH₂)_(q)—Y¹-(C₁-C₆)alkyl,—(CH₂)_(q)—Y¹—(CH₂)_(t)—A¹ or —(CH₂)_(q)—Y¹—(CH₂)_(t)-(C₃-C₇)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R¹ areoptionally substituted with (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy,carboxyl, —CONH₂, —S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester,1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y¹ is O, S(O)_(m),—C(O)NX⁶—, —CH═CH—, —C≡C—, —N(X⁶)C(O)—, —C(O)NX⁶—, —C(O)O—, —OC(O)N(X⁶)—or —OC(O)—; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH₂)_(q)group and (CH₂)_(t) group in the definition of R¹ are optionallyindependently substituted with hydroxy, (C₁-C₄)alkoxy, carboxyl, —CONH₂,—S(O)_(m)(C₁-C₆)alkyl, —CO₂(C₁-C₄)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or3 fluoro groups or 1 or 2 (C₁-C₄)alkyl groups; R^(1A) is selected fromthe group consisting of hydrogen, F, Cl, Br, I, (C₁-C₆)alkyl,phenyl(C₁-C₃)alkyl, pyridyl(C₁-C₃)alkyl, thiazolyl(C₁-C₃)alkyl andthienyl(C₁-C₃)alkyl, provided that R^(1A) is not F, Cl, Br or I when aheteroatom is vicinal to C″; R² is hydrogen, (C₁-C₈)alkyl,-(C₀-C₃)alkyl-(C₃-C₈)cycloalkyl, -(C₁-C₄)alkyl-A¹ or A¹; where the alkylgroups and the cycloalkyl groups in the definition of R² are optionallysubstituted with hydroxy, —C(O)OX⁶, —C(O)N(X⁶)(X⁶), —N(X⁶)(X⁶),—S(O)_(m)(C₁-C₆)alkyl, —C(O)A¹, —C(O)(X⁶), CF₃, CN or 1, 2 or 3independently selected halo groups; R³ is selected from the groupconsisting of A¹, (C₁-C₁₀)alkyl, -(C₁-C₆)alkyl-A¹,-(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, -(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl,-(C₁-C₅)alkyl-X¹-(C₀-C₅)alkyl-A¹ and-(C₁-C₅)alkyl-X¹-(C₁-C₅)alkyl-(C₃-C₇)cycloalkyl; where the alkyl groupsin the definition of R³ are optionally substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1, 2, 3, 4 or 5 independently selectedhalo groups or 1, 2 or 3 independently selected —OX³ groups; X¹ is O,S(O)_(m), —N(X²)C(O)—, —C(O)N(X²)—, —OC(O)—, —C(O)O—, —CX²═CX²—,—N(X²)C(O)O—, —OC(O)N(X²)— or —C≡C—; R⁴ is hydrogen, (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl, or R⁴ is taken together with R³ and the carbon atomto which they are attached and form (C₅-C₇)cycloalkyl,(C₅-C₇)cycloalkenyl, a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen, or is a bicyclicring system consisting of a partially saturated or fully saturated 5- or6-membered ring, fused to a partially saturated, fully unsaturated orfully saturated 5- or 6-membered ring, optionally having 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, sulfur and oxygen; X⁴ is hydrogen or (C₁-C₆)alkyl or X⁴ istaken together with R⁴ and the nitrogen atom to which X⁴ is attached andthe carbon atom to which R⁴ is attached and form a five to sevenmembered ring; R⁶ is a bond or is

where a and b are each independently 0, 1, 2 or 3; X⁵ and X^(5a) areeach independently selected from the group consisting of hydrogen, CF₃,A¹ and optionally substituted (C₁-C₆)alkyl; the optionally substituted(C₁-C₆)alkyl in the definition of X⁵ and X^(5a) is optionallysubstituted with a substituent selected from the group consisting of A¹,OX², —S(O)_(m)(C₁-C₆)alkyl, —C(O)OX², (C₃-C₇)cycloalkyl, —N(X²)(X²) and—C(O)N(X²)(X²); or the carbon bearing X⁵ or X^(5a) forms one or twoalkylene bridges with the nitrogen atom bearing R⁷ and R⁸ wherein eachalkylene bridge contains 1 to 5 carbon atoms, provided that when onealkylene bridge is formed then only one of X⁵ or X^(5a) is on the carbonatom and only one of R⁷ or R⁸ is on the nitrogen atom and furtherprovided that when two alkylene bridges are formed then X⁵ and X^(5a)cannot be on the carbon atom and R⁷ and R⁸ cannot be on the nitrogenatom; or X⁵ is taken together with X^(5a) and the carbon atom to whichthey are attached and form a partially saturated or fully saturated 3-to 7-membered ring, or a partially saturated or fully saturated 4- to8-membered ring having 1 to 4 heteroatoms independently selected fromthe group consisting of oxygen, sulfur and nitrogen; or X⁵ is takentogether with X^(5a) and the carbon atom to which they are attached andform a bicyclic ring system consisting of a partially saturated or fullysaturated 5- or 6-membered ring, optionally having 1 or 2 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; Z¹ is a bond, O or N—X², provided that when a and b are both 0then Z¹ is not N—X² or O; or R⁶ is—(CR^(a)R^(b))_(a)—E—(CR^(a)R^(b))_(b)—, where the —(CR^(a)R^(b))_(a)group is attached to the carbonyl carbon of the amide group of thecompound of formula I and the —(CR^(a)R^(b))_(b) group is attached tothe terminal nitrogen atom of the compound of Formula I; E is —O—, —S—,—CH═CH— or an aromatic moiety selected from

said aromatic moiety in the definition of E optionally substituted withup to three halo, hydroxy, —N(R^(c))(R^(c)), (C₁-C₆)alkyl or(C₁-C₆)alkoxy; R^(a) and R^(b) are, for each occurrence, independentlyhydrogen, (C₁-C₆)alkyl, trifluoromethyl, phenyl or monosubstituted(C₁-C₆)alkyl where the substituents are imidazolyl, naphthyl, phenyl,indolyl, p-hydroxyphenyl, —OR^(c), S(O)_(m)R^(c), C(O)OR^(c),(C₃-C₇)cycloalkyl, —N(R^(c))(R^(c)), —C(O)N(R^(c))(R^(c)), or R^(a) orR^(b) may independently be joined to one or both of R⁷ or E (where E isother than O, S or —CH═CH—) to form an alkylene bridge between theterminal nitrogen and the alkyl portion of the R^(a) or R^(b) and the R⁷or E group, wherein the bridge contains 1 to 8 carbon atoms; or R^(a)and R^(b) may be joined to one another to form a (C₃-C₇)cycloalkyl;R^(c), for each occurrence, is independently hydrogen or (C₁-C₆)alkyl; aand b are independently 0, 1, 2 or 3, with the proviso that if E is —O—or —S—, b is other than 0 or 1 and with the further proviso that if E is—CH═CH—, b is other than 0; R⁷ and R⁸ are each independently hydrogen oroptionally substituted (C₁-C₆)alkyl; where the optionally substituted(C₁-C₆)alkyl in the definition of R⁷ and R⁸ is optionally independentlysubstituted with A¹, —C(O)O-(C₁-C₆)alkyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5halo groups, 1 to 3 hydroxy groups, 1 to 3 —O—C(O)(C₁-C₁₀)alkyl groupsor 1 to 3 (C₁-C₆)alkoxy groups; or R⁷ and R⁸ can be taken together toform —(CH₂)_(r)—L—(CH₂)_(r)—; where L is C(X²)(X²), S(O)_(m) or N(X²);R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, fluoro, hydroxy and (C₁-C₅)alkyl optionally independentlysubstituted with 1-5 halo groups; R¹¹ is selected from the groupconsisting of (C₁-C₅)alkyl and phenyl optionally substituted with 1-3substituents each independently selected from the group consisting of(C₁-C₅)alkyl, halo and (C₁-C₅)alkoxy; R¹² is selected from the groupconsisting of (C₁-C₅)alkylsulfonyl, (C₁-C₅)alkanoyl and (C₁-C₅)alkylwhere the alkyl portion is optionally independently substituted by 1-5halo groups; A¹ for each occurrence is independently selected from thegroup consisting of (C₅-C₇)cycloalkenyl, phenyl, a partially saturated,fully saturated or fully unsaturated 4- to 8-membered ring optionallyhaving 1 to 4 heteroatoms independently selected from the groupconsisting of oxygen, sulfur and nitrogen and a bicyclic ring systemconsisting of a partially saturated, fully unsaturated or fullysaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen, fused to a partially saturated, fully saturated or fullyunsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, sulfur andoxygen; A¹ for each occurrence is independently optionally substituted,on one or optionally both rings if A¹ is a bicyclic ring system, with upto three substituents, each substituent independently selected from thegroup consisting of F, Cl, Br, I, OCF₃, OCF₂H, CF₃, CH₃, OCH₃, —OX⁶,—C(O)N(X⁶)(X⁶), —C(O)OX⁶, oxo, (C₁-C₆)alkyl, nitro, cyano, benzyl,—S(O)_(m)(C₁-C₆)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy,phenylalkyloxy, halophenyl, methylenedioxy, —N(X⁶)(X⁶), —N(X⁶)C(O)(X⁶),—S(O)₂N(X⁶)(X⁶), —N(X⁶)S(O)₂-phenyl, —N(X⁶)S(O)₂X⁶, —CONX¹¹X¹²,—S(O)₂NX¹¹X¹², —NX⁶S(O)₂X¹², —NX⁶CONX¹¹X¹², —NX⁶S(O)₂NX¹¹X¹²,—NX⁶C(O)X¹², imidazolyl, thiazolyl and tetrazolyl, provided that if A¹is optionally substituted with methylenedioxy then it can only besubstituted with one methylenedioxy; where X¹¹ is hydrogen or optionallysubstituted (C₁-C₆)alkyl; the optionally substituted (C₁-C₆)alkyldefined for X¹¹ is optionally independently substituted with phenyl,phenoxy, (C₁-C₆)alkoxycarbonyl, —S(O)_(m)(C₁-C₆)alkyl, 1 to 5 halogroups, 1 to 3 hydroxy groups, 1 to 3 (C₁-C₁₀)alkanoyloxy groups or I to3 (C₁-C₆)alkoxy groups; X¹² is hydrogen, (C₁-C₆)alkyl, phenyl,thiazolyl, imidazolyl, furyl or thienyl, provided that when X¹² is nothydrogen, the X¹² group is optionally substituted with one to threesubstituents independently selected from the group consisting of Cl, F,CH₃, OCH₃, OCF₃ and CF₃; or X¹¹ and X¹² are taken together to form—(CH₂)_(r)—L¹—(CH₂)_(r)—; L¹ is C(X²)(X²), O, S(O)_(m) or N(X²); r foreach occurrence is independently 1, 2 or 3; X² for each occurrence isindependently hydrogen, optionally substituted (C₁-C₆)alkyl oroptionally substituted (C₃-C₇)cycloalkyl, where the optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X² are optionally independently substituted with—S(O)_(m)(C₁-C₆)alkyl, —C(O)OX³, 1 to 5 halo groups or 1-3 OX³ groups;X³ for each occurrence is independently hydrogen or (C₁-C₆)alkyl; X⁶ foreach occurrence is independently hydrogen, optionally substituted(C₁-C₆)alkyl, (C₂-C₆)halogenated alkyl, optionally substituted(C₃-C₇)cycloalkyl, (C₃-C₇)-halogenated cycloalkyl, where optionallysubstituted (C₁-C₆)alkyl and optionally substituted (C₃-C₇)cycloalkyl inthe definition of X⁶ is optionally independently mono- or di-substitutedwith (C₁-C₄)alkyl, hydroxy, (C₁-C₄)alkoxy, carboxyl, CONH₂,—S(O)_(m)(C₁-C₆)alkyl, carboxylate (C₁-C₄)alkyl ester or1H-tetrazol-5-yl; or when there are two X⁶ groups on one atom and bothX⁶ are independently (C₁-C₆)alkyl, the two (C₁-C₆)alkyl groups may beoptionally joined and, together with the atom to which the two X⁶ groupsare attached, form a 4- to 9-membered ring optionally having oxygen,sulfur or NX⁷ as a ring member; X⁷ is hydrogen or (C₁-C₆)alkyloptionally substituted with hydroxy; m for each occurrence isindependently 0, 1 or 2; with the provisos that: 1) X⁶ and X¹² cannot behydrogen when attached to C(O) or S(O)₂ in the form C(O)X⁶, C(O)X¹²,S(O)₂X⁶ or S(O)₂X¹²; and 2) when R⁶ is a bond then L is N(X²) and each rin the definition —(CH₂)_(r)—L—(CH₂)_(r)— is independently 2 or 3; b) asecond pharmaceutical composition comprising an additional compounduseful for treating a condition selected from the group consisting ofgastroesophageal reflux disease, gastroparesis, postoperative ileus,emesis, constipation and colonic pseudo-obstruction; and c) a container.